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The GABAergic system in schizophrenia

The GABAergic system in schizophrenia A defect in neurotransmission involving c-amino butyric acid (GABA) in schizophrenia was ®rst proposed in the early 1970s. Since that time, a considerable effort has been made to ®nd such a defect in components of the GABAergic system. After a brief introduction focusing on historical perspectives, this paper reviews post- mortem and other biological studies examining the following components of the GABAergic system in schizophrenic subjects : the GABA biosynthetic enzyme, glutamate decarboxylase ; free GABA ; the GABA transporter ; the GABA , GABA and benzodiazepine receptors ; and the catabolic enzyme GABA A B transaminase. Additionally, post-mortem studies using morphology or calcium-binding protein to identify GABAergic neurons are also reviewed. Substantial evidence argues for a defect in the GABAergic system of the frontal cortex in schizophrenia which is limited to the parvalbumin-class of GABAergic interneurons. Received 18 July 2001 ; Reviewed 11 November 2001 ; Revised 28 January 2002 ; Accepted 30 January 2002 Key words : CSF, GABA, post-mortem, schizophrenia. Historical perspectives use GABA in neurotransmission (Bloom and Iversen, 1971). In the monkey cortex approx. 25 % of the neurons The physiologists Ernst and Friedrich Weber (1845), Ivan in most regions are GABAergic ( Jones, 1990). In addition Pavlov (1885) and Wilhelm Biedermann (1887) estab- to the neocortex, signi®cant populations of glutamate lished the concept of inhibition in the nervous system and decarboxylase (GAD)- or GABA-immunoreactive (IR) cell lead to the identi®cation of inhibitory neurons by Cornelis bodies or axon terminals have also been identi®ed in Wiersma (1933) (Florey, 1991). Roberts and Frankel primate brain regions including the midbrain (Holstein et (1950), Awapara et al. (1950), and Udenfriend (1950) al., 1986 ; Okada et al., 1971), hippocampal formation reported the isolation of c-aminobutyric acid (GABA) (Schlander et al., 1987), the thalamus (Smith et al., 1987b), from animal brain material. Working on cray®sh stretch the basal ganglia (Smith et al., 1987a), and the amygdala receptors initially and later with the monosynaptic knee- (Sorvari et al., 1995). jerk re¯ex in cats, Ernst Florey reported that a Factor I had GABA was ®rst implicated in the pathophysiology of inhibitory effects in these systems (Florey and McLennan, schizophrenia by Eugene Roberts in 1972. He proposed 1955). Factor I was later puri®ed from beef brain and that a susceptibility to schizophrenia might be due to a shown to be identical to GABA (Bazemore et al., 1957). defect in the inhibitory GABAergic neurons control of The status of GABA as neurotransmitter was not widely neural circuits governing behavioral responses. This accepted until further studies in crustaceans established defect would be exacerbated under stressful conditions in that GABA was the most common inhibitory substance in which increased monoaminergic drive would increase the CNS (Dudel, 1963), that peripheral inhibitory but not disinhibitory input onto those GABA neurons, producing excitatory neurons contained high GABA concentrations abnormalities of perceptual and cognitive integration (Kravitz et al., 1963), that inhibitory motor neurons (Roberts, 1972). Since this initial proposal, a role for released GABA (Otsuka et al., 1966), and that GABA is GABA in the pathophysiology of schizophrenia continues removed from the postsynaptic cleft by an uptake process to be formulated in the context of complex interactions (Orkand and Kravitz, 1971). between GABA and other neurotransmitter systems. GABA is the major inhibitory neurotransmitter in the Carlsson (1988) proposed a model of psychosis that mammalian brain ; up to 30 % of cortical neurons in rats involves multiple neurotransmitters including a defective GABA-mediated inhibition of glutamatergic feedback Address for correspondence : Dr B. P. Blum, New York State inhibition of mesolimbic dopamine function and describes Psychiatric Institute, Department of Neuroscience, 1051 Riverside a defect in thalamic ®ltering of sensory and arousal input Drive, Unit 42, New York, NY, 10032, USA. to the cortex (see also Carlsson et al., 2001). An Tel. : 212-543-6223 Fax : 212-543-6017 abnormality in GABAergic regulation of dopamine cell E-mail : bb453!columbia.edu 160 B. P. Blum and J. J. Mann burst ®ring has been postulated to underlie the symptoms agents have generally not been demonstrated to produce of schizophrenia (Grace, 1991 ; Moore et al., 1999). antipsychotic effects in of themselves (Wassef et al., Others have noted, in the direct modulation of the 1999). In-vivo pharmacological manipulation of the dopaminergic system by GABAergic neurons, a potential GABAergic system indicates that GABAergic function is mechanism whereby an abnormality in the GABAergic potentially relevant to the pathophysiology of schizo- system could be involved in the dopaminergic dys- phrenia. For example, blockade of GABA receptors with function of schizophrenia (Carlsson, 1988 ; Fuxe et al., picrotoxin in the prefrontal cortex of rats impairs 1977 ; Garbutt and van Kammen, 1983 ; Stevens et al., sensorimotor gating, an effect that is reversed by 1974 ; van Kammen, 1979). Squires and Saederup (1991) haloperidol (Japha and Koch, 1999). Conversely, en- postulated that schizophrenia involved a GABAergic hancement of GABAergic activity by either c-vinyl- predominance caused by either hyperactive GABA GABA (GVG) or lorazepam in baboons inhibits dopamine receptors or hypoactive glutamate receptors and}or transmission in the striatum as indicated by increased destruction of counterbalancing glutamatergic neurons by [""C]raclopride binding (Dewey et al., 1992). Furthermore, neurotropic pathogens. This last model has received little GVG treatment has been shown to increases phencycli- ongoing support. dine-induced release of dopamine in a dose-dependent Olney and Farber (1995) developed a model of manner in the rat prefrontal cortex but not in the striatum schizophrenia in which a state of ` NMDA receptor (Schiffer et al., 2001). Hypofunctioning of the GABAergic hypofunction ' is caused by either intrinsically hypofunc- system may be responsible for the striatal dopamine tioning NMDA receptors or through excitotoxic loss of overactivity and behavioural changes noted in schizo- NMDA receptor-bearing GABAergic neurons. This state phrenic subjects (Breier et al., 1997). results in excessive dopaminergic input into corticolimbic The purpose of this paper is to review the data regions (also see Carlsson et al., 2001) with resultant from post-mortem and other biological studies of the further hypofunctioning of the glutamatergic system GABAergic system in schizophrenia in order to provide a through feedback mechanisms. Several classes of com- synthesis of what is known. pounds, including benzodiazepines (BZD), muscurinic receptor antagonist and haloperidol, blocked NMDA- induced neurotoxicity in the posterior cingulate and GAD retrospenial regions of experimental animals. Loss of GABAergic interneurons in the hippocampal formation, GAD, the rate-limiting biosynthetic enzyme of GABA, possible secondary to excitotoxic injury (Benes, 1999) or catalyses the decarboxylation of glutamic acid to yield to loss of glutamatergic neurons has also been hypo- GABA. Two major isoenzymes of GAD, named GAD '& thesized (Deakin and Simpson, 1997). Similarly, Deutsch and GAD , based on their approximate molecular weight '( et al. (2001) postulates a failure of GABAergic inhibition of 65±4 and 66±6 kDa respectively, have been identi®ed in of the AMPA}kainite class of glutamatergic receptor with human brain (Bu et al., 1992). GAD is preferentially '& a resultant cascade of excitotoxic events. localized in axon terminals (Esclapez et al., 1994), more A dysfunction of a7-nicotinic acetylcholine receptor tightly membrane associated and more often exists in an on GABA interneurons in the hippocampus (Adler et al., inactive apoGAD form (lacking the cofactor pyridoxal 1998) or disruption of interactions between the choliner- phosphate) compared with the GAD isoenzyme (Kauf- '( gic system and 5-HT receptor on GABAergic inter- man et al., 1991). In rat hippocampus, most cells express neurons in the frontal cortex (Dean, 2001) has been transcripts of both GAD isoenzymes (Stone et al., 1999). proposed as sites of pathophysiology in schizophrenia. It has been suggested that GAD might preferentially '& Relationships between epilepsy, schizophrenia and the synthesize GABA for vesicular release and that GAD '( GABAergic system have been proposed (Keverne, 1999 ; may be preferentially involved in synthesis of cytoplasmic Stevens, 1999). Effects of the GABAergic system in GABA (Erlander and Tobin 1991 ; Esclapez et al., 1994 ; neuro- and in particular cortico-developmental processes Feldblum et al., 1993). have been integrated into developmental hypotheses of Early efforts to detect an abnormality in the GABAergic psychosis and schizophrenia. GABAergic interneurons system focused on determining activity levels of GAD. form the substrate for the gamma frequency oscillations Seven such studies were performed on cortical tissue postulated to synchronize brain activity in disparate homogenates from parts of the temporal and frontal regions of the brain and an abnormality in such may cause lobes : all but two of which reported no signi®cant psychosis (for a review see Keverne, 1999). difference between controls and patients with schizo- Although there is some evidence for a role for BZD and phrenia in these regions (see Table 1a) (Bennett et al., valproate in the treatment of schizophrenia, GABAergic 1979 ; Bird et al., 1977 ; Cross and Owen, 1979 ; Crow et The GABAergic system in schizophrenia 161 Table 1a. GABAergic presynaptic markers in schizophrenia Marker Area Finding Comment Author GAD activity Hippocampus 5 McGeer and McGeer (1977) BA 11, 37, 38 5 BA 7 i 35 %* BA 18 i 43 %* BA 34 i 39 %* GAD activity Hippocampus i 48±2 %* Bird et al. (1977) N. accumbens i 44 %* Putamen i 27 %* Amygdala i 46 %* GAD activity Hippocampus 5 Perry et al. (1978) BA 21 5 BA 10 5 GAD activity Frontal cortex 5 Found i GAD Crow et al. (1978) with j PMI GAD activity Frontal cortex 5 Cross and Owen (1979) Amygdala 5 GAD activity Multiple brain regions 5 Spokes (1980) GAD activity Frontal cortex 5 Bennett et al. (1979) GAD activity BA 9 5 Hanada et al. (1987) GAD mRNA BA 9 i 40 %* Layer I Akbarian et al. (1995b) '( i 48 %* Layer II i 30 %* Layers III±V GAD }b-actin BA 22 i 70 %* Impagnatiello et al. (1998) '( immunoreactivity GAD }b-actin BA 22 i ns '& immunoreactivity GAD mRNA-positive BA 9 i 25±35 %* Layers III±V Volk et al. (2000) '( neuron densities Ratio of GAD BA 9 i 68 %* n ¯ 6 Guidotti et al. (2000) '( mRNA to neuron-speci®c enolase mRNA level GAD protein level BA 9 i 54 %* n ¯ 15 '( GAD protein level BA 9 5 n ¯ 15 '& GAD -IR puncta Hippocampus 5 Todtenkopf and Benes (1998) '& GAD -IR puncta BA 10 5 Benes et al. (2000) '& BA 24 5 * Indicates ®ndings reported as signi®cant by original authors (and throughout all tables). ns, not signi®cant. al., 1978 ; McGeer and McGeer, 1977 ; Perry et al., 1978 ; as comorbidity, medication and smoking history, diag- Spokes, 1980). One of the divergent studies found nostic heterogeneity and cause-of-death effects were signi®cantly lower GAD activity in the sensory as- not clearly addressed. Although some studies have sociation, calcarine ®ssure and insular cortex in the indicated that GAD is stable in human brain during schizophrenic group compared with controls but not in routine post-mortem handling (Spokes, 1979 ; Spokes et many other cortical and subcortical regions (McGeer and al., 1979), Crow et al. (1978) found a signi®cant negative McGeer, 1977). The second divergent study found correlation between GAD activity levels and PMI. signi®cantly lower GAD activity in patients with schizo- Although GAD activity levels is signi®cantly decreased in phrenia in all areas examined : amygdala, hippocampus, brain material obtained from patients dying of protracted nucleus accumbens, and putamen (Bird et al., 1977). illness (McGeer et al., 1971 ; McGeer and McGeer 1976 ; Whereas post-mortem interval (PMI) and age were Spokes 1979 ; Spokes et al., 1979), most of the studies controlled for in this study, other possible confounds such mentioned above did not control for this potential effect. 162 B. P. Blum and J. J. Mann A later study of GAD activity in frontal cortex [Brodmann mRNA-labelled neurons in cortical layers III±V was found area (BA) 9] and caudate from chronic schizophrenics also in the schizophrenic group compared with the controls. revealed no abnormality (Hanada et al., 1987). This study However, mean grain density per neuron did not also reported lower GAD activity in the subgroup of signi®cantly differ across the two groups. Additionally controls that had died after a prolonged terminal illness comparison of chronic haloperidol- and benztropine (PTI). The control and chronic schizophrenic group were mesylate-treated Cynomolgus monkeys with untreated fairly well matched for age, length of PMI and sex ratios. controls indicated that this medication treatment does not Before interpreting studies examining GAD gene affect GAD mRNA expression. '( expression by in-situ hybridization, it is important to note Reelin is a protein which regulates cortical cell that GAD protein levels may not match GAD mRNA positioning and}or movement during development and levels because of a variety of transcriptional, translational which appears to be expressed preferentially in and post-translational modi®cations. For example, in- GABAergic interneurons in the adult human neocortex creases in GABA levels decreases GAD activity but (Curran and D 'Arcangelo, 1998 ; Impagnatiello et al., '( does not alter GAD mRNA levels nor GAD activity 1998). Reelin protein and mRNA levels were found to be '( '& in rats (Rimvall et al., 1993 ; Rimvall and Martin, 1994). 40±50 % lower in schizophrenic subjects compared with Also, elevation of GABA by vigabatrin treatment affects controls in the prefrontal cortex (BA 10 and BA 46), GAD protein levels differently in various brain regions temporal cortex (BA 22), hippocampus, caudate and '( of the rat (Sheikh and Martin, 1998). cerebellum (Impagnatiello et al., 1998). This study also A study measured GAD mRNA in human prefrontal reported signi®cantly (E 70 %) lower GAD }b-actin but '( '( cortex by in-situ hybridization in order to determine if a not GAD }b-actin IR optical densities in the schizo- '& postulated decrease in GABA in this region was due phrenic subjects compared with controls. either to decreased gene expression or to a decrease in the A recent study measured GAD , GAD , and reelin '& '( number of GABAergic cells (Akbarian et al., 1995b). Ten mRNA levels by quantitative reverse transcriptase- schizophrenic subjects were compared to ten age, gender polymerase chain reaction and GAD and GAD protein '& '( and autolysis-time matched controls. Subjects with in- levels in brains from schizophrenic, bipolar and depressed complete medical records, substance abuse histories or subjects. Reelin mRNA, GAD protein and mRNA were '( prolonged agonal states were excluded. Fewer GAD signi®cantly lower in the prefrontal cortex and cerebellum '( mRNA-expressing neurons with no signi®cant overall in schizophrenic and psychotic bipolar but not in unipolar loss of neurons were found in cortical layers I±V of the depressed subjects without psychosis compared to normal schizophrenic subjects compared with controls. The controls (Guidotti et al., 2000). GAD mRNA levels did '& GAD mRNA levels, as measured by optical densities of not differ across the diagnostic groups. Reelin and GAD '( '( ®lm autoradiographs, were signi®cantly lower in cortical levels were found to be unrelated to PMI or neuroleptic layers II, III, IV and V of the schizophrenic subjects treatment history. compared with controls. The authors expressed doubt The distribution of GAD -immunoreactive (GAD - '& '& that the lower mRNA levels of the schizophrenic subjects IR) puncta in the hippocampus was examined in a group were secondary to neuroleptic treatment by noting that of 13 schizophrenic subjects and 13 age-, gender- and the single neuroleptic-naive schizophrenic subject had the PMI-matched controls (Todtenkopf and Benes, 1998). No lowest mRNA values. signi®cant difference was found in the density of GAD - '& A second study examined GAD mRNA expression in IR puncta in contact with pyramidal or non-pyramidal '( the prefrontal cortex of 10 schizophrenic subjects and 10 cells or dispersed within the neuropil of the layers CA1±4. sex-matched controls (Volk et al., 2000). The schizo- However, a signi®cant positive correlation was found phrenic group did not signi®cantly differ from the control between the density of GAD -IR puncta in contact with '& group with respect to age, PMI, brain pH or storage time. pyramidal and non-pyramidal cells and neuroleptic ex- One control and four schizophrenic subjects had lifetime posure in the schizophrenic subjects. This ®nding and the diagnoses of alcohol or other substance abuse and one fact that the two neuroleptic-naive schizophrenic subjects control subject had a lifetime diagnosis of depressive had the lowest density of GAD -IR puncta led the '& disorder not otherwise speci®ed. Seven schizophrenic and authors to speculate that schizophrenics might inherently nine control subjects had sudden deaths occurring outside have lowered density of GABAergic terminals in certain of a hospital ; one schizophrenic subject was a suicide regions of the hippocampus. victim. This study used in-situ hybridization followed by The density of GAD -IR terminals in layers II±VI of '& counts of silver grains within neuronal soma from the cingulate and prefrontal cortices did not differ between randomly selected cortical sites within speci®c laminar the groups (Todtenkopf and Benes, 1998) ; however, the levels. Signi®cantly (25±35 %) lower density of GAD density of GAD -IR terminals was signi®cantly lower in '( '& The GABAergic system in schizophrenia 163 layers II±IV of ®ve bipolar subjects (added in this study) section above) examined multiple cortical and subcortical compared with the normal controls (Benes et al., 2000). regions and noted lower levels only in the posterior Overall, neuroleptic treatment history did not appear to portion of the hippocampus of the schizophrenic group. correlate with terminal densities in the schizophrenic Spokes et al. (1980) found lower GABA concentrations in group. A two-dimensional counting method was used. the nucleus accumbens and the amygdala of the schizo- Three studies report lower GAD mRNA expression phrenic group compared with the controls. Absolute '( and two studies report lower GAD protein levels GABA levels in this study were in agreement with a study '( indicating that schizophrenia may be associated with less by Cross et al. (1979) but tended to be an order of GAD gene expression in the prefrontal cortex. Total magnitude higher than the other studies. In contrast to the '( GAD activity and GAD -immunoreactivity do not study of Perry et al. (1979), Cross and colleagues found no '& appear to be altered in schizophrenia. However, it should difference in GABA levels in the nucleus accumbens and be noted that the amount of GAD protein is 3- to 8-fold thalamus between the study groups. Ohnuma et al. '& greater than the amount of GAD protein in most rat (1999), using a more speci®c brain region de®nition than '( brain regions (Sheikh et al., 1999). One possibility is that the studies of Korpi et al. (1987), Perry et al. (1989), or the abnormality in schizophrenia is restricted to GAD Kutay et al. (1989), reported lower GABA levels in BA 9 '( and is not detectable by measurement of total GAD and 10, but not 11. The PMI was longer in the control enzyme activity. Moreover, there is evidence that the group than in the six schizophrenic subjects and possible GAD de®cit is limited to subset of neurons in the group sex and medication effects were not ruled out. '( prefrontal cortex (Volk et al., 2000). Nevertheless, this remains an interesting study as it reported a speci®c regional GABA level abnormality that was paralleled by increase in GABA receptor a subunit GABA concentrations " mRNA and decrease in GAT-1 mRNA (see below). The search for a GABAergic defect in schizophrenia also While most studies report low GABA levels in at least stimulated examination of GABA concentrations, both in some brain regions in schizophrenia, there is no clear brain tissue (see Table 1b) and in cerebrospinal ¯uid (CSF). consensus on the affected brain regions except for a GABA concentrations in brain tissue are unaffected by consistent ®nding of lower GABA in the amygdala (3 out agonal status (Spokes et al., 1979) but rise rapidly 1±2 h of 3 studies). Measurement of total GABA levels may be after death. The rise in GABA levels may continue even insufficiently sensitive to consistently detect a GABAergic 24 h post-mortem (Perry et al., 1981). Free CSF GABA defect affecting only a subpopulation of GABAergic cells. levels are unaffected by agonal status but decline The ®ndings of lower GABA in the amygdala in signi®cantly with age (Perry et al., 1979 ; Spokes et al., schizophrenia is interesting in light of recently reported 1979). Most studies controlled for age and post-mortem rat model in which a experimentally induced GABAergic processing, however drug history was not consistently dysfunction in the amygdala induces changes in the controlled for and the study of Perry et al. (1979) included GABAergic system of the hippocampus. The subregional a number of controls with various neurological illnesses. distribution of these changes is similar to ®ndings in Using a single-cation exchange column method lower previous post-mortem studies of schizophrenia (Benes, GABA concentrations was found in the nucleus accum- 1999 ; Berretta et al., 2001). bens and thalamus from schizophrenics compared with control (Perry et al., 1979). Another study used the same CSF studies method and did not ®nd lower GABA concentrations in the nucleus accumbens, medial dorsal thalamus, frontal Nine published studies examined GABA concentrations cortex or caudate of the schizophrenic subjects compared in CSF. The majority reported no difference between with controls (Perry et al., 1989). The authors suggested controls and schizophrenic patients (see Table 2). One that the ®rst study was ¯awed by lack of anatomical study found lower baseline CSF levels in a group of accuracy with respect to dissection of the nucleus schizophrenics compared with controls ; however it is not accumbens and the thalamus. Korpi et al. (1987) found no clear if a number of schizoaffective patients (previously effect of diagnosis on GABA levels in the nucleus mentioned in the report) were included in this group accumbens, frontal cortex, and caudate, but GABA was (Sternberg, 1980). If so, perhaps depression explained the 37±5 % lower in the amygdala in the schizophrenic group lower CSF GABA levels. All patients were drug free for compared with controls. Kutay et al. (1989) found lower 2 wk prior to the baseline lumbar puncture and GABA GABA levels in multiple brain regions including the levels showed no relationship with age, sex, or degree of amygdala, the hippocampus, frontal pole, superior tem- psychosis. This study also reported that a trial of pimozide poral cortex and thalamus. Toru et al. (1988) (see GAD increased GABA levels in the patients. Van Kammen et al. 164 B. P. Blum and J. J. Mann Table 1b. Presynaptic markers Marker Area Finding Comment Author GABA concentration Frontal cortex 5 Korpi et al. (1987) N. accumbens 5 Amygdala i 37±5%* GABA concentration Frontal pole i 40 % n ¯ 7 SCZ, Kutay et al. (1989) Hippocampus i 45 % 4 controls Sup. temp. cortex i 48 % Inf. temp. cortex 5 Amygdala i 61 % Dorsal thalamus i 72 % GABA concentration Frontal cortex 5 Perry et al. (1989) N. accumbens 5 Mediodorsal thalamus 5 GABA concentration Thalamus 5 Cross et al. (1979) N. accumbens 5 GABA concentration Thalamus i 21 %* Perry et al. (1979) N. accumbens i 35 %* GABA concentration Hippocampus 5 Spokes et al. (1980) Amygdala i 31±9%* N. accumbens i 13 % i 25 %* early Ventrolateral thalamus 5 onset cases only GABA concentration Dentate gyrus 5 n ¯ 7 Toru et al. (1988) CA 1±3 5 Subiculum 5 Post. hippocampus i 25 %* Sup., inf., and med. 5 temporal gyri Medial frontal and 5 orbitofrontal cortex GABA concentration BA 9 i 44 %* PMI controls " Ohnuma et al. (1999) BA 10 i 25 %* PMI SCZ BA 11 5 GABA-transaminase Amygdala 5 Sherif et al. (1992) Hippocampus 5 Serum GABA- 5 White et al. (1980) transaminase Serum GABA- 5 Reveley et al. (1980) transaminase GABA release BA 34 i 77±3%* n ¯ 5 Sherman et al. (1991) GABA release BA 8 i 68±9 %* Homogenate Sherman et al. (1991) (veratridine induced) GABA uptake sites BA 11 5 Simpson et al. (1989) ([ H]nipecotic acid) BA 38 i 18±9 %* left side Hippocampus i bilat.** Amygdala i bilat.** GABA uptake sites Hippocampus i 24 % left side Reynolds et al. (1990) ([$H]nipecotic acid) i 29 %* left side Sudden death cases i 21 % right side Amygdala 5 GABA uptake sites BA 11 5 Simpson et al. (1992a) ([$H]nipecotic acid) BA 38 i left side 15 % Males j right side 15±7% The GABAergic system in schizophrenia 165 Table 1b (cont.) Marker Area Finding Comment Author GABA uptake sites Putamen i bilat. E 50 %* Simpson et al. (1992b) ([ H]nipecotic acid) caudate N. accumbens 5 Globus pallidus 5 GABA uptake sites Ant. cingulate ; 5 Simpson et al. (1998a) ([ H]nipecotic acid) Ant. precentral 5 gyrus GABA uptake sites Putamen (head) 5 ([ H]nipecotic acid) Putamen (tail) j* Manchester collection Simpson et al. (1998b) Caudate j* Manchester and Gothenburg collection Globus pallidus 5 GAT-1 mRNA BA 9 i 18±1 %* Tissue sections Ohnuma et al. (1999) BA 10 5 BA 11 5 Table 2. CSF and serum GABA ®ndings in schizophrenia Measure Finding Comment Author GABA, CSF 5 n ¯ 17 schizophrenics, Lichtshtein et al. (1978) concentration 9 control GABA, CSF 5 n ¯ 7 schizophrenic, Gold et al. (1980) concentration 5 schizoaffective, 2 other psychosis, compared with neurological control group GABA, CSF i* n ¯ 17 schizoaffective Sternberg (1980) concentration and schizophrenic GABA, CSF 5 n ¯ 11 schizophrenic, Gerner and Hare (1981) concentration 29 controls GABA, CSF 5 between untreated and n ¯ 17 controls, Zimmer et al. (1981) concentration controls 9 untreated}7 treated j GABA in CSF schizophrenics with long-term neuroleptic tx. GABA, CSF j 45±7 %* In chronic schizophrenic McCarthy et al. (1981) concentration subset only GABA, CSF 5 all schizophrenic n ¯ 25 drug-free schizophrenic and van Kammen et al. (1982) concentration i 26 %* female pts only 5 schizoaffective GABA, CSF 5 n ¯ 20 chronic schizophenics Gerner et al. (1984) concentration GABA, CSF 5 n ¯ 19 schizophrenic Perry et al. (1989) concentration GABA, CSF and i plasma but not n ¯ 62 chronic van Kammen et al. (1998) plasma levels CSF GABA associated schizophenics with prefrontal but not global sulcal widening Plasma GABA 5 n ¯ 15 schizophrenics Petty and Sherman (1984) Platelet GABA- 5 n ¯ 22 schizophrenics Reveley et al. (1980) transaminase level Platelet GABA 5 n ¯ 14 schizophrenics White et al. (1980) transaminase level 166 B. P. Blum and J. J. Mann (1982) noted a signi®cant decrease in the female schizo- failed to ®nd any signi®cant difference in platelet GABA- phrenic sub-population compared to female controls while transaminase levels between schizophrenics and controls also reporting a tendency towards increased GABA levels (Reveley et al., 1980 ; White et al., 1980). No signi®cant with increased length of illness. That elevation of CSF effect of sex, psychotic state, length of illness or GABA levels may be correlated with length of schizo- medication treatment was noted in the study by White et phrenic illness ®nds support in a study by McCarthy et al. al. (1980) ; Reveley et al. (1980) reported no correlation (1981) in which a sub-population of chronic schizo- between age or sex and GABA-transaminase levels. Sherif phrenics had higher GABA levels compared to controls. et al. (1992) measured GABA-transaminase in brain However, Gerner et al. (1984) did not corroborate this homogenates from various regions including hippocam- suggestion. An increase in CSF GABA levels has been pus, amygdala, cingulate and frontal gyrus and found no found after 30 d treatment with sulpride and to be signi®cant difference between controls and undifferentiat- correlated with long-term neuroleptic treatment (Zimmer ed schizophrenics. Thus, there is no evidence of altered et al., 1981). However, Lichtshtein et al. (1978) noted a catabolism of GABA in schizophrenia. small but signi®cant decrease in CSF GABA levels after 2 months of neuroleptic treatment while Gattaz et al. (1986) GABA release and uptake observed no change in free CSF GABA levels in schizophrenic patients after 3 months of haloperidol Synaptosomal preparations are used in the study of treatment. Lastly, Zander et al. (1981) reported that synaptic function and neurotransmission in animal models. stopping chronic anti-psychotic medication treatment Synaptosomal preparations obtained up to 24 h post- produced no change in CSF GABA levels. CSF GABA is mortem from human brains are metabolically active and lowered in depressed patients and therefore comorbidity can release various neurotransmitters after veratrine must be considered in interpretation of these studies stimulation (Hardy et al., 1982). Using this model, (Gerner and Hare, 1981 ; Gold et al., 1980). A later study Sherman et al. (1991) compared schizophrenics and by Van Kammen et al. (1998) found that plasma GABA controls, with PMI of 20³7 h (mean³s.d.) and 23³7h, levels showed a signi®cant negative correlation with both respectively, and reported a signi®cantly lower veratri- prefrontal sulcal widening and ventricle}brain ratio on CT dine-induced release of glutamate and GABA but not scans but not to global sulcal widening in patients with aspartate in synaptosomes from temporal and frontal schizophrenia. CSF GABA levels did not correlate with cortex of the schizophrenic group. these CT measures but did show a negative correlation The concentration and duration of a neurotransmitter with age and age of onset. The disassociation between in the synaptic cleft is mostly regulated by rate of uptake CSF and serum GABA level is puzzling. One would by transporter proteins. Four GABA transporters have so expect CSF GABA to re¯ect brain pathology better than far been described (GAT-1, GAT-2, GAT-3 and BGT-1), plasma. Moreover, the plasma GABA ®nding may not be each varying in its localization pattern and pharma- correct since plasma GABA levels were not found to be cological pro®le (Borden, 1996). Simpson et al. (1989) lower in patients with schizophrenia (Petty and Sherman, reported signi®cantly lower binding of [$H]nipecotic acid 1984). to GABA-uptake sites in the left BA 38 (polar temporal), CSF GABA is not clearly lower in schizophrenia. There bilaterally in the amygdala and hippocampus in schizo- are insufficient studies in which the possible confounds of phrenic subjects compared to controls (see Table 1). This anti-psychotic medication treatment, comorbidity (in study did have sufficient numbers of age-matched subjects particular affective disorders), length of illness and sex are and controls with similar PMI ; agonal state effects were all controlled. Additionally, while pharmacological studies said to have been minimized by selection of subjects who in animals suggest that total CSF GABA concentrations had died acutely and were matched for cause of death. are mostly related to brain GABA (Bohlen et al., 1979 ; Possible medication in¯uence could not be entirely ruled Ferkany et al., 1979), it remains unknown to what degree out, although the authors reported that binding data from this is true in humans. A defect limited to a speci®c subjects that were drug-free were indistinguishable from subtype of GABAergic neurons, such as the chandelier those treated with neuroleptics. subtype (see below), may not be re¯ected in CSF GABA Comparing schizophrenic subjects to age- and PMI- levels. matched controls, Reynolds et al. (1990) found lower [$H]nipecotic acid binding in both groups in the left hippocampus compared to the right side but not so in the GABA-transaminase amygdala. The schizophrenic group tended towards lower Two studies measuring GABA-transaminase, the principal binding values in the left hippocampus compared with catabolic enzyme for GABA in the mammalian brain, controls (p ¯ 0±08) ; this tendency became statistically The GABAergic system in schizophrenia 167 signi®cant when subgroups of sudden-death cases were distribution and appear to be sufficiently sensitive to compared. The rationale for this distinction was that detect impaired input. There are approx. 100 times more nipecotic acid binding may be reduced in patients with GABA terminals on the apical dendrites than on the chronic respiratory illnesses (Czudek and Reynolds, 1990). proximal axon segment. Lewis et al. (2000) reported a Simpson et al. (1992a) used [$H]nipecotic acid to de®cit of the chandelier GABAergic neurons, which measure GABA-uptake sites in a series of schizophrenic speci®cally target the proximal axon segment. Such a and control brains in which cerebral atrophy had been localized GABAergic input defect may not be equally previously established and reported higher [$H]nipecotic detectable by assays of GAT, GAD, brain GABA or CSF acid binding in both groups in the right compared with GABA. left BA 38, lower left BA 38 binding and increased putaminal binding in the schizophrenic brains compared GABA receptors with controls. Subcortical GABA-uptake sites were further studied by Simpson et al. (1992b) in brains of 19 Two types of GABA receptors have been identi®ed in the schizophrenic subjects who had died with the diagnosis of human brain : the GABA receptor, which is associated schizophrenia along with 22 neuropsychiatrically normal with a chloride channel and mediates fast inhibitory controls, matched for age, gender ratio and PMI. In synaptic transmission and the GABA receptor which is contradiction to the above study, an approx. 50 % lower associated with potassium and calcium channels and is a [$H]nipecotic acid binding was seen in the putamen G protein-linked metabotrobic receptor (Bowery, 2000 ; bilaterally in the schizophrenic group. The binding of this Olsen and Homanics, 2000). The GABA receptor is ligand did not differ between the two groups in the thought to be a heteropentameric glycoprotein composed caudate, globus pallidum or nucleus accumbens. This of subunits of six distinct subclasses : a, b, c, d, e and q, the study also reported no correlation between binding to largest being the a subclass which includes six known GABA-uptake sites and length of the neuroleptic-free members (a ). In the adult mammalian brain, the subunit " ' period in a subgroup of medication-free schizophrenics. combination of a b c is thought to be the most common " # # Simpson et al. (1998a) measured [$H]nipecotic acid (Olsen and Homanics, 2000). binding to GABA-uptake sites in 11 brain regions from a Bennett et al. (1979) used tritiated GABA as a ligand group of 12 neuroleptic-treated chronic schizophrenia (9 (see Table 3) and reported that post-mortem binding in males, 3 females) and a group of normal controls (14 frontal cortex homogenates of schizophrenics was not males, 5 females). No signi®cant overall difference was signi®cantly different from controls. The study did report noted between the two groups in any of the 11 temporal alterations in serotonergic receptor binding. Control and and frontal lobe areas. The authors suggested these schizophrenia groups were not well matched for age or ®ndings might be in¯uenced by low uptake measurements sex ratio. The authors reported no correlation between in three of the female controls and large variance in the PMI or time frozen and receptor-binding results ; however hippocampal data. agonal and possible drug effects could not be excluded. A recent study examined [$H]nipecotic acid binding in Hanada et al. (1987) measured GABA receptor binding the basal ganglia from three brain collections (Manchester, using the GABA agonist [$H]muscimol and observed Gothenburg and Runwell) (Simpson et al., 1998b). The signi®cantly higher binding (B ) in both caudate and BA max schizophrenic (n ¯ 12±18) and the control subjects (n ¯ 9 in the chronic schizophrenic group as a whole compared 19±22) did not differ with respect to age, PMI or storage with controls. This ®nding survived subdivision into time. [$H]Nipecotic acid binding was higher in the sudden death and PTI subgroups in both regions of the schizophrenic groups compared to controls in the heads sudden-death subgroup but not in the caudate of the PTI of the caudate and putamen of the Manchester collection. subgroup. Higher binding was also noted in the caudate of the Benes et al. (1992) examined GABA receptor binding female schizophrenic subjects of the Gothenburg col- in the anterior cingulate gyrus in order to test a hypothesis lection ; the caudate-binding values obtained from this that upregulation of these receptors would follow the loss collection were 2- to 3-fold greater than those seen in the of cortical interneurons reported to occur in this region Manchester collection. Caudate-binding values were not and the prefrontal cortex of chronically psychotic patients reported for the Runwell collection. (Benes et al., 1991). By using a bicuculline-sensitive Several studies indicate that GABA uptake may be [$H]muscimol binding assay and a nuclear-track, coverslip- moderately lower in both the hippocampus ([$H]nipecotic emulsion technique, they counted autoradiographic grains acid binding studies) and in BA 9 (GAT-1 mRNA studies, per neuron and per 200 lm# of neuropil. [$H]Muscimol see below) of schizophrenic subjects compared with binding on neuronal cell bodies is 84 % higher in layer II controls. GABA-uptake sites may re¯ect GABA terminal and 74 % higher in layer III in the schizophrenic group 168 B. P. Blum and J. J. Mann Table 3. Postsynaptic markers Marker Area Finding Comment Author GABA receptor Frontal cortex 5 Homogenate Bennett et al. (1979) binding ([ H]GABA) GABA receptor BA 9 j 32 %* Homogenate Hanada et al. (1987) binding ([ H]muscimol) GABA receptor Cingulate cortex j 84 %* L II Tissue sections Benes et al. (1992) binding (bicuculline- j 74 %* L III sensitive [ H]muscimol) j 43 %* L II GABA receptor BA10 j 70 %* L II Benes et al. (1996a) binding (bicuculline- j 44 %* L III sensitive [ H]muscimol) j 48 %* L V j 90 %* L II large neurons j 66 %* L VI j 135 %* L VI sm. non-pyram. GABA receptor Area dentate Benes et al. (1996b) binding ([ H]muscimol) Molecular j 20±40 % Granular j 40±60 %* CA4, subiculum j 60±80 %* presubiculum j 60±80 %* CA3 j 74±90 %* j non-pyramidal cells 3x " pyram. CA1 j 22±36 % GABA receptor BA 9 j 18±5 %* Dean et al. (1999) binding ([ H]muscimol) GABA receptor BA 46 5 Akbarian et al. (1995a) subunit mRNAs GABA receptor BA 46 i 28 % (both isoforms) Huntsman et al. (1998) subunit mRNAs i 51±7%* (c S) (c S and c L) i 16±9% (c L) n ¯ 5 # # # GABA receptor BA 9 j 49±1%* n ¯ 6 Ohnuma et al. (1999) subunit mRNA BA 10 j 32±5% (p ¯ 0±051) BA 11 j 36±7% (p ¯ 0±0) GABA receptor Dentate gyrus Not quantitated Mizukami et al. (2000) immunoreactivity CA1-4 n ¯ 5 BZD receptor sites Medial, inferior i (p ! 0±01) Homogenates Kiuchi et al. (1989) [ H]¯unitrazepam and superior temporal gyri CA1-3 i (p ! 0±05) Dentate gyrus 5 BA 9, 10, 46 j 25 % BA 45 and 47 j (p ¯ 0±05 %) BA 11 and 12 j (p ¯ 0±01 %) BZD receptor sites Hippocampus i 29±0%* Homogenates Squires et al. (1993) [ H]¯unitrazepam Frontal cortex 5 n ¯ 3 BZD receptor sites Hippocampus 5 Homogenates Reynolds and Stroud (1993) [ H]¯unitrazepam BZD receptor sites BA 10 5 Homogenates Pandey et al. (1997) [ H]RO15-1788 BZD receptor sites Area dentate 5 Tissue sections Benes et al. (1997) [ H]-¯unitrazepam Subiculum j 20±30 %* Presubiculum j 15±20 %* CA1 5 CA2 5 CA3 (s. oriens only) j 30 %* CA4 5 The GABAergic system in schizophrenia 169 compared to normal controls. In layer I neuropil [$H] [$H]muscimol to GABA receptors, as well as decreased muscimol was increased in the schizophrenic group. PMIs [$H]ketanserin binding to 5-HT receptors in BA 9 of were similar in the two groups ; however, group sex ratios schizophrenic subjects compared to controls. The groups and cause of death were not mentioned. The schizophrenic were well matched for donor age, PMI, tissue pH and time group was signi®cantly younger than the control group frozen ; analysis of covariance showed that these potential but the authors discounted the possibility of a confound- confounds as well as ®nal neuroleptic dose did not effect ing effect as both younger and older schizophrenics had the comparison of ligand binding between the groups. elevated numbers of receptor sites compared to controls. Potential effects of agonal states were not addressed. The authors believed that elevation of [$H]muscimol In animal experiments, reduced neuronal activity can binding was not secondary to neuroleptic treatment, as a lead to decreased gene expression for a number of neuroleptic-naive and a minimally exposed patient both GABA receptor subunits (Hendry et al., 1990, 1994 ; had elevated binding. Huntsman et al., 1994). Akbarian et al. (1995a) used in-situ Benes et al. (1996b) also used a bicuculline-sensitive hybridization histochemisty to quantitate mRNA of the [$H]muscimol-binding assay to examine GABA receptor GABA receptor subunits a , a , a , b , b and c in the A A " # & " # # levels in the prefrontal cortex (BA 10) of 7 schizophrenic prefrontal cortex. The schizophrenic and control groups subjects and 16 normal controls. No difference in average showed similar laminar gene expression patterns with size of neuronal cell bodies was observed between the highest a , b , and c expression in layers III and IV, " # # two groups ; however, more grains per cell were found on highest a and b expression in layer II, and higher a # " & the large (pyramidal) neurons of layers II±VI (greatest in expression in layers IV±VI with peak expression in layer layer II) and on the small (non-pyramidal) neurons of layer IV. No signi®cant difference in expression of any of the VI in the schizophrenic subjects compared with controls. subunit genes was noted between the two groups. The 12 Although the control group was signi®cantly older and schizophrenic and 12 control subjects were matched for had a signi®cantly shorter mean PMI compared to the age, sex and PMI. schizophrenic group, no correlation was found between Huntsman et al. (1998) used in-situ hybridization these potential confounds and GABA binding. Two histochemisty and semi-quantitative reverse transcrip- schizophrenic subjects without history of neuroleptic tion±PCR to measure the relative abundance of two exposure had binding values that were lower than the species of mRNA of the c subunit of the GABA neuroleptic-treated schizophrenics and similar to the receptor in the prefrontal cortex of ®ve matched pairs of average of the control group. These same two neuroleptic- schizophrenics and controls. The c subunit, which is free schizophrenic subjects had exhibited a higher layer II necessary for high-affinity BZD binding, exists in two GABA receptor-binding value in a previous study of the forms : short (c S) and long (c L), which differ by a # # anterior cingulate gyrus (Benes, 1992) compared with the functionally signi®cant 8-amino-acid insert. The laminar schizophrenic group as a whole indicating that the higher pattern of c subunit mRNA labelling was consistent with GABA receptor binding in the prefrontal cortex of the past reports for both schizophrenics and controls. Al- schizophrenic group may not be simply a medication though the schizophrenic group was found to have lower effect. c message labelling in each of the six cortical levels, this Benes et al. (1996a), using brain tissue from the same difference reached statistical signi®cance in only layers II subjects in the above study (with the addition of one and III. The authors reported a lower level (average subject to the schizophrenia group), reported higher 51±7%, p ! 0±001) of short (c S) mRNA (but only 16±9% [$H]muscimol in subregions of the hippocampus of the lower long (c L) mRNA) in the prefrontal cortex of the schizophrenic group compared with controls. Increases of schizophrenic group compared with their matched con- 90 % (stratum oriens of CA3), of 74 % (stratum pyrami- trols. The authors speculated that this relative overabun- dales of CA3), of 60±73 % (subiculum and presubiculum) dance of the long (c L) mRNA in the prefrontal cortex of and of 22±36 % were seen in the CA1 subregion (ranges schizophrenics would result in GABA receptors of indicating layer differences within a subregion). Increased decreased functionality. Agonal effects were not discussed GABA binding in the subregion CA3 was limited to but the authors expressed concern about possible medi- non-pyramidal cells while binding increases in the CA1 cation effects. subregion were noted only on pyramidal cells. The author Ohnuma et al. (1999) measured a subunit mRNA postulated that these subregional increases in GABA expression in BA 9, 10, and 11 of 6 schizophrenics and 12 receptor binding might re¯ect increased vulnerability of controls and found a general increase in the schizophrenic certain subpopulation of GABAergic neurons to injury group which attained statistical signi®cance in the large during development. cells of layer V of BA 9 and in layer III of BA 10. The Dean et al. (1999) reported increased binding of patient group was comprised of neuroleptic-treated 170 B. P. Blum and J. J. Mann chronic schizophrenics who had a shorter averaged PMI controls with matching sex compositions and ages. than controls. Medication history was not reported. One study examined the anatomical distribution of Squires et al. (1993) found lower [$H]¯unitrazepam immunolabelled GABA receptors in the hippocampus of binding in a schizophrenic group compared with controls, 5 chronic schizophrenics and 3 controls matched for age with differences reaching statistical signi®cance in the and PMI (Mizukami et al., 2000). Schizophrenic subjects somatomotor and cingulate cortex but not in other were reported to be resistant to neuroleptic treatment ; cortical regions such as the frontal cortex. Lower binding however cause of death and treatment status at time of in the schizophrenic group was also noted in the globus death were not reported. The authors found less immuno- pallidus, hippocampus and cerebellar cortex (vermis) but labelling of the mossy cells in CA4 and the pyramidal cells not in the putamen. The authors speculated that these in CA1±3 in the schizophrenic subjects compared to the reductions in binding might represent the loss of gluta- controls. The granule cells of the dentate gyrus appeared matergic (pyramidal) cells. Four of 15 schizophrenic unstained in the schizophrenic subjects whereas staining subjects were suicide victims whereas the nine controls in controls was reported as moderate. In all regions the were victims of traffic accidents. Past studies of BZD degree of staining of interneurons was similar in both receptors in suicide victims found altered (Cheetham et al., subject types. 1988) and unaltered binding (Manchon et al., 1987 ; In summary, GABA receptor binding is higher in Rochet et al., 1992 ; Stocks et al., 1990) ; therefore the use schizophrenia in cortical regions generally regarded as of suicide victims may be a confound. The schizophrenic important in the pathophysiology of schizophrenia. subjects were reported to be drug-free for months prior to Somewhat at odds with this observation is the tendency death ; the average PMI appears to have been signi®cantly towards less subunit mRNA in the prefrontal cortex of longer for the schizophrenic group (Squires et al., 1993). schizophrenic subjects in two studies. These receptor To further study the relationships between suicide, changes may represent upregulation in response to schizophrenia and BZD receptor binding, Pandey et al. reduced GABAergic input. What remains unclear is the (1997) examined binding of the selective, high-affinity functional signi®cance of alterations in binding or gene radioligand [$H]RO15-1788 in prefrontal cortex B max expression. The functional response mediated by these values (BA 10) homogenates from 13 suicide victims receptors may be impaired and counteract the bene®ts of without schizophrenia, 8 schizophrenic suicide victims, 5 up-regulation. Studies of receptor coupling and signal non-suicide schizophrenic subjects and 15 normal con- transduction are needed. trols. The B of BZD receptors in the prefrontal cortex max was higher in suicide victims, largely due to increased B in the suicide victims who had died by violent max means. Overall, the B of the schizophrenic subjects did max BZD binding studies not differ from controls ; however, the sample size was The therapeutic efficacy of BZDs as anxiolytic agents is small. attributed to their ability to potentiate GABA receptor- Benes et al. (1997) assayed BZD binding with [$H]¯uni- mediated inhibition by increasing the receptors affinity trazepam in hippocampal tissue sections from the same for GABA. Selectivity of BZD binding to the GABA schizophrenic and control subjects used in a previous receptor is determined by speci®c amino-acid residues study (Benes et al., 1996a). After normalization of the in the c and the a subunits (Mohler et al., 2000). data, the ratios of BZD binding to GABA binding in Kiuchi et al. (1989) assayed [$H]¯unitrazepam binding controls was similar throughout most of the hippocampal in homogenates from multiple cortical regions of brains region except in the inner and outer molecular layers of from schizophrenic and control subjects and reported the area dentata where higher BZD binding was observed. signi®cantly higher binding in the medial frontal cortex [$H]Flunitrazepam binding was found to be only modestly orbitofrontal cortex, orbital cortex, medial and inferior higher in the stratum oriens of the CA3, the subiculum temporal gyri, cornu Ammonis 1±3 of the hippocampus and the presubiculum of the schizophrenic subjects com- and putamen of the schizophrenic subjects compared with pared with controls. As the magnitude of these increases controls (see Table 3). No signi®cant differences in binding did not match the increases in GABA binding in these were found in other areas. Medication effects might be a regions, the authors speculated that the regulation of the confound in this study and agonal state issues were BZD-binding elements might be uncoupled from the regu- unaddressed. lation of the GABA receptor. The authors noted that Reynolds and Stroud (1993) found no difference in such an uncoupling phenomena was reported in the cere- [$H]¯unitrazepam binding in hippocampal homogenates bellum of the stagger mouse (Luntz-Leybman et al., 1995). between a group of 15 schizophrenic subjects and normal Taken as a group, these papers on BZD binding in schizo- The GABAergic system in schizophrenia 171 phrenia do not provide a consensus about BZD binding pyramidal cell output ; they also appear to receive direct in examined regions of the frontal or temporal lobes. synaptic input from mesocortical dopamine and thalamo- cortical glutamatergic projection (Muly III et al., 1998 ; Sesack et al., 1995, 1998). Calcium-binding proteins as markers of GABAergic An early study of calcium-binding proteins in schizo- neurons phrenia used CR and calbindin (CB) immunohistochemical In the prefrontal cortex of primates, sub-populations of labelling of tissue from prefrontal cortical areas 9 and 46 GABAergic interneurons can be classi®ed based on obtained from 1 schizoaffective and 4 schizophrenic morphological characteristics, synaptic targets or the subjects and 5 controls matched for age, sex and PMI (see presence of different calcium-binding proteins (Conde! et Table 4) (Daviss and Lewis, 1995). One of the schizo- al., 1994 ; Lund and Lewis, 1993). The calcium-binding phrenic subjects died by suicide ; the cause of death listed protein parvalbumin is found primarily in the wide-basket for the remainder of subjects are consistent with short and chandelier subclasses of GABA neurons. The axon agonal periods. The authors found a 50±70 % greater terminals of the chandelier neurons synapse on the initial density of the CB-immunoreactive (CB-IR) and a 10±20 % axon segments of pyramidal cell. The axon terminals of (non-signi®cant) greater density of the CR-immunoreac- the wide- basket neurons synapse on the cell bodies and tive (CR-IR) non-pyramidal neurons of both cortical areas dendrites of pyramidal cells. GABA neurons in the double- in the schizophrenic group compared with the controls. bouquet subclass contain calretinin (CR) and have terminal The authors noted small sample size, lack of stereological axons that synapse onto the dendritic shafts of both methodology and potential medication effects as caveats. pyramidal and non-pyramidal neurons. The parvalbumin- Beasley and Reynolds (1997) used a monoclonal containing GABA neurons of the chandelier subclass have antibody against parvalbumin to quantitate parvalbumin- attracted the most scrutiny in studies of schizophrenia containing chandelier and wide-basket GABA neurons in because their synaptic targeting of the axon initial tissue sections from BA 10 obtained from schizophrenic segment of pyramidal cells suggest a strong in¯uence on and control subjects. The authors reported fewer parval- Table 4. Calcium protein markers of non-pyramidal neurons in schizophrenia Marker Area Finding Comment Author Non-pyramidal neurons BA 9 and 46 Daviss and Lewis (1995) Calbindin-IR j 50±70 %* Calretinin-IR j 10±20 % Parvalbumin-IR neurons BA 10 i* layer III Beasley and Reynolds (1997) i* layer IV Parvalbumin-IR neurons BA 9 5 Woo et al. (1997) BA 46 5 BA 17 5 Parvalbumin-IR neurons Ant. cingulate j layers Va±Vb Kalus et al. (1997) cortex GAT-1-IR cartridges BA 9 i 40 %* Woo et al. (1998) (chandelier cells) BA 46 i 40 %* GAT-1-IR cartridges BA 46 i 27±7 %* layer II±IIIb Pierri et al. (1999) (chandelier cells) i 31±5 %* layer IIIb±IV 5 layer VI Parvalbumin-IR neurons BA 9 and 5 Results previously Lewis (2000) BA 46 reported in Woo et al. (1997) GAT-1-IR cartridges BA 9 and i 40 %* Results previously Lewis (2000) (chandelier cells) BA 46 reported inWoo et al. (1998) Parvalbumin-IR neurons BA 9 and i* Reynolds and Beasley (2001) BA 46 Calbindin-IR neurons i* Calretinin-IR neurons 5 172 B. P. Blum and J. J. Mann bumin-positive cells in the schizophrenic subjects com- 30 schizophrenics [15 of the comparison triads had been pared with the normal controls. Differences reached used in a previous study (Woo et al., 1998)] had statistical signi®cance only in layers III and IV. No group signi®cantly lower GAT-1-IR cartridge density in layers difference was found in cortical thickness. Age, sex, and II±IIIa and IIIb±IV. The schizophrenic subjects were duration of illness did not have an effect on cell counts. matched to controls by sex, age and PMI. Signi®cant The authors did not use a stereological method. The numbers of subjects in both the schizophrenia group and question of an effect of neuroleptics on parvalbumin psychiatric control group but not the normal control expression and cell counts was left open. group had histories of substance abuse or were suicide Woo et al. (1997) examined parvalbumin-IR local victims. Medication effects were not apparent on GAT-1- circuit GABAergic neurons in tissue sections from BA 9, IR cartridge density in prefrontal cortex of male Cynomol- 46 (prefrontal) and 17 (visual) obtained from 15 schizo- gus monkeys were treated for 9±12 months with phrenic subjects and sex-matched controls and detected haloperidol decanoate and benztropine mesylate. no signi®cant difference in their densities between the GAT-1 mRNA levels were quantitated in 10 pairs of schizophrenics and controls. As the authors found no schizophrenic subjects and controls (see Volk et al., 2000) somal size differences between the two subject groups, in a study which sought to determine if lower GAT-1 the inability to perform absolute cell counts was not density in the prefrontal cortex was accompanied by thought to be a confound. However, differences in lower GAT-1 gene expression (Volk et al., 2001). A neuropil or tissue shrinkage could be critical for density threshold of 2-fold background was used to exclude non- measures. Cause of death and medication histories of the speci®c labelling and a somal size criterion of greater than subjects were not reported. 50 lm# was used to exclude glial cells. GAT-1 mRNA- More parvalbumin-IR GABA interneurons in layers Va positive neuron density was lower (21±33 %) in layer I, and Vb of the anterior cingulate cortex was found in layer II, the super®cial portion of layer III, and at the schizophrenics compared with controls, but the density of boundary of layers III±IV in the schizophrenic group Nissl-stained neuron pro®les did not differ in any of the compared with controls. Grain density per neuron was layers (Kalus et al., 1997). Stereological methods were not also signi®cantly decreased (11 %, p ¯ 0±009) in the employed. The two groups differed signi®cantly in schizophrenic group only at the layers III±IV border and average PMI ; disparities in tissue shrinkage, medication cross-sectional size did not differ signi®cantly between histories and agonal states may have confounded the the two groups. This study also compared GAT-1 mRNA results. labelling between 4 haloperidol- and benztropine mesy- Woo et al. (1998) used an antibody against the GABA late-treated Cynomolgus monkeys and 4 untreated con- transporter GAT-1 to identify the distinctive vertical trols and reported that after 9±12 months of treatment arrays of chandelier axons known as cartridges. This there were no signi®cant differences. The authors con- study included 15 schizophrenic subjects matched by age, cluded that GAT-1 expression in the prefrontal cortex of sex and PMI to both a normal control and a non- schizophrenics is unaltered overall, but that it may be schizophrenic psychiatric group. The relative density of lower in the chandelier class of GABAergic cells. The GAT-1-IR cartridges, assessed by stereological methods, authors noted that lower density of GAT-1 mRNA- was lower in the schizophrenic subjects across layers II-VI positive neurons is congruent with a previous ®nding of in both BA 9 and 46 compared with both the psychiatric laminar-speci®c decreases in GAD -positive neuronal '( and normal controls. Density of CR-IR axon boutons in but not synaptophysin-mRNA-positive neuronal densi- layers II±IIIa did not differ between the schizophrenic and ties (Volk et al., 2000). normal control subjects. The schizophrenic group included Overall, it appears that there may be fewer GAT-1-IR two suicide victims, the psychiatric group included 12 axon cartridges consistent with less GABAergic inhibition suicide victims and normal control group had no suicide at the proximal axon segment of pyramidal cells by cases ; cause of death in the remaining subjects was not parvalbumin-positive chandelier cells. Of the calcium- reported. The majority of the schizophrenic group had binding proteins, parvalbumin alone is expressed later in been treated with neuroleptic medication ; however, the foetal development in GABAergic interneurons. Late authors noted that two of the schizophrenic subjects who expression of parvalbumin is hypothesized to lead to a had been off medications for a signi®cant time before ` window of vulnerability ' in which an insult to the foetus death also had GAT-1 cartridge densities that were lower leads to glutamate receptor stimulation and cytotoxic than control densities. calcium in¯ux (Reynolds and Beasley, 2001). An important Pierri et al. (1999) also examined the laminar densities question to be resolved is whether or not the abnormality of GAT-1-IR cartridges and found that in comparison in the parvalbumin-class interneurons involves a loss of with a psychiatric and a normal control group, a group of such cells (Beasley and Reynolds, 1997 ; Reynolds and The GABAergic system in schizophrenia 173 Beasley, 2001) or is limited to a decrease in the number of that a GABAergic defect may be speci®c for the chandelier axon cartridges (Pierri et al., 1999). Of the calcium-protein class interneurons (Beasley and Reynolds, 1997 ; Lewis, positive GABAergic interneurons in the adult mouse 2000 ; Reynolds et al., 2000). Fewer chandelier-class cortex, parvalbumin-class interneurons alone do not GABAergic synapsing onto cortical pyramidal cells may express reelin protein, suggesting that the abnormality in contribute to impaired ability to perform dopamine- this class of interneurons is not related to the de®cits in dependent functions such as working memory (Goldman- reelin reported in schizophrenia (Alca! ntara et al., 1998 ; Rakic, 1996 ; Lewis et al., 1999). Decreases in dopamine Guidotti et al., 2000 ; Impagnatiello et al., 1998). input into the prefrontal cortex may also lead to decreased cortical glutamatergic input to the ventral striatum} ventral pallidum. This may lead to a decrease in tonic Non-pyramidal cell counts dopamine release resulting in a decreased ability to A non-stereological study of 9 chronic schizophrenic, 9 regulate phasic dopamine release in mesolimbic circuits schizoaffective and 12 control subjects reported fewer leading to positive symptoms (Grace, 1991 ; Moore et al., small neurons in layers I and II of the prefrontal cortex 1999). Alternatively, a decrease in cortical glutamatergic (BA 10) and in layers II±VI of the anterior cingulate (BA activity onto striatal GABAergic projection neurons may 24) in the two patient groups compared with controls lead to a decrease in the inhibitory effects of the indirect (Benes et al., 1991) These decreases tended to be greater striatothalmic pathway on the thalamus. Such an effect in the schizoaffective subgroup. Glial cell numbers did not may decrease the ability of the thalamus to ®lter off differ between the groups nor did pyramidal cell numbers excessive or irrelevant stimuli (Carlsson et al., 2001). except in layer V of the patient group in which had Some evidence is also presented for the existence of signi®cantly higher counts were observed. GABAergic defect in regions of the temporal lobe, in A recent stereological study of post-mortem tissue particular in the hippocampus. In this region, there also from the hippocampus obtained from 10 schizophrenic appears to be de®cits in GABA uptake (Reynolds et al., and 10 age- and PMI-matched controls found fewer 1990 ; Simpson et al., 1989) with increased (and possibly numbers of non-pyramidal cells in CA2 sector of the compensatory) GABA receptor binding (Benes et al., schizophrenics compared with controls (Benes et al., 1996a). Studies of BZD receptor binding have generated 1998). A similar ®nding was reported in a group of four con¯icting results in both frontal cortical regions and in bipolar patient also included in this study. Numbers of the hippocampus. The only study employing the use of pyramidal cells did not differ between the groups. Three tissue sections reported modest regional increases in of the schizophrenic subjects were suicide victims and hippocampal BZD binding in the schizophrenic group both groups may have been partly composed of subjects that suggest an uncoupling of the BZD and GABA with prolonged agonal intervals. Two schizophrenic receptors (Benes et al., 1997). Whether or not this re¯ects subjects who were neuroleptic-free for at least 1 yr also a true uncoupling of the BZD and GABA receptors and had decreased non-pyramidal counts in the sector CA2. is related to an abnormality in c-subunit processing There may be fewer non-pyramidal neurons in the (Huntsman et al., 1998) remains to be determined. prefrontal cortex in schizophrenia, further evidence of a The full anatomical distribution of post-mortem ®nd- GABAergic de®cit. ings in the GABAergic system in schizophrenia is not known with certainty because most studies have selec- tively examined certain regions. Systematic mapping Conclusion studies of the human neocortex are lacking for most Substantial evidence argues for a defect in the GABAergic GABAergic markers. The authors also wish to emphasize system of the frontal cortex in schizophrenia, particularly that many of the ®ndings reviewed in this article remain in the prefrontal region and to a lesser degree in the unreplicated. Interpretation of abnormal ®ndings in the anterior cingulate gyrus. A coherent pattern can be GABAergic system in schizophrenia should be tempered described : lower GAD mRNA and protein (Akbarian et by lack of information on functional changes in '( al., 1995b ; Guidotti et al., 2000 ; Impagnatiello et al., GABAergic transmission, the awareness that schizophre- 1998 ; Volk et al., 2000) is possibly paralleled by lower nia may be a heterogeneous set of disorders and that GABA concentrations (Kutay et al., 1989), less release of multiple defects may cause the same basic illness. One GABA (Sherman et al., 1991), lower GAT-1 mRNA also needs to keep in mind the likely complexity of the (Ohnuma et al., 1999 ; Volk et al., 2001) and up-regulation GABAergic system ; a system in which the major synthetic of GABA sites (Benes et al., 1992, 1996b ; Dean et al., enzyme occurs in two distinct forms at the genomic level, 1999 ; Hanada et al., 1987). the number of recognized receptor subtypes is approx. 20 Use of calcium-binding proteins as markers indicates (Olsen and Homanics, 2000). Complexity is also added by 174 B. P. Blum and J. J. Mann the fact that GABAergic neurons interact with multiple Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL (1991). De®cits in small interneurons in prefrontal and neurotransmitters systems, exist in at least 14 distinct cingulate cortices of schizophrenic and schizoaffective electrophysiological subtypes (Gupta et al., 2000) and are patients. Archives of General Psychiatry 48, 996±1001. involved in virtually every brain circuit. Additionally, one Benes FM, Todtenkopf MS, Logiotatos P, Williams M (2000). needs to use caution in interpreting ®ndings from any Glutamate decarboxylase -immunoreactive terminals in study that has not controlled for medication history. For '& cingulate and prefrontal cortices of schizophrenic and example, chronic haloperidol treatment increases the size bipolar brain. Journal of Chemical Neuroanatomy 20, of GABA-IR axosomatic terminals in the medial prefrontal 259±269. cortex of rats (Vincent et al., 1994) and increases GABA Benes FM, Vincent SL, Alsterberg G, Bird ED, SanGiovanni JP receptor binding in the substantia nigra, the latter effect (1992). Increased GABA receptor binding in super®cial being partially reversed after 8 d of treatment cessation layers of cingulate cortex in schizophrenics. Journal of (Huffman and Ticku, 1983). Part of the antipsychotic Neuroscience 12, 924±929. effects of medications such as haloperidol may be due to Benes FM, Vincent SL, Marie A, Khan Y (1996b). Up- such secondary changes in the GABAergic system. regulation of GABA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 75, 1021±1031. Benes FM, Wickramasinghe R, Vincent SL, Khan Y, References Todtenkopf M (1997). Uncoupling of GABA and Adler LE, Olincy A, Waldo M, Harris JG, Griffith J, Stevens benzodiazepine receptor binding activity in the K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman hippocampal formation of schizophrenic brain. Brain R (1998). Schizophrenia, sensory gating, and nicotinic Research 755, 121±129. receptors. Schizophrenia Bulletin 24, 189±202. Bennett Jr. JP, Enna SJ, Bylund DB, Gillin JC, Wyatt RJ, Akbarian S, Huntsman MM, Kim JJ, Tafazzoli A, Potkin SG, Snyder SH (1979). Neurotransmitter receptors in frontal Bunney Jr. WE, Jones EG (1995a). GABA receptor subunit cortex of schizophrenics. Archives of General Psychiatry 36, gene expression in human prefrontal cortex : comparison of 927±934. schizophrenics and controls. Cerebral Cortex 5, 550±560. Berretta S, Munno DW, Benes FM (2001). Amygdalar Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, activation alters the hippocampal GABA system, ` partial ' Bunney Jr. WE, Jones EG (1995b). Gene expression for modelling for postmortem changes in schizophrenia. Journal glutamic acid decarboxylase is reduced without loss of of Comparative Neurology 431, 129±138. neurons in prefrontal cortex of schizophrenics. Archives of Bird ED, Spokes EG, Barnes J, MacKay AV, Iversen LL, General Psychiatry 52, 258±266. Shepherd M (1977). Increased brain dopamine and reduced Alcantara S, Ruiz M, D'Arcangelo G, Ezan F, de Lecea L, glutamic acid decarboxylase and choline acetyl transferase Curran T, Sotelo C, Soriano E (1998). Regional and cellular activity in schizophrenia and related psychoses. Lancet 2, patterns of reelin mRNA expression in the forebrain of the 1157±1158. developing and adult mouse. Journal of Neuroscience 18, Bloom FE, Iversen LL (1971). Localizing $H-GABA in nerve 7779±7799. terminals of rat cerebral cortex by electron microscopic Awapara J, Landua AJ, Fuerst R, Seale B (1950). Free c- autoradiography. Nature 229, 628±630. aminobutyric acid in the brain. Journal of Biological Bo$ hlen P, Huot S, Palfreyman MG (1979). The relationship Chemistry 187, 35±39. between GABA concentrations in brain and cerebrospinal Bazemore AW, Elliott KAC, Florey E (1957). Isolation of ¯uid. Brain Research 167, 297±305. Factor I. Journal of Neurochemistry 1, 334±339. Borden LA (1996). GABA transporter heterogeneity, Beasley CL, Reynolds GP (1997). Parvalbumin- pharmacology and cellular localization. Neurochemistry immunoreactive neurons are reduced in the prefrontal International 29, 335±356. cortex of schizophrenics. Schizophrenia Research 24, Bowery N (2000). GABA Receptors : structure and function. 349±355. In : Martin D, Olsen R (Eds.), GABA in the Nervous System, Benes FM (1999). Evidence for altered trisynaptic circuitry in The View at Fifty Years (pp. 233±244). Philadelphia : schizophrenic hippocampus. Biological Psychiatry 46, Lippincott Williams & Wilkins. 589±599. Breier A, Su TP, Saunder R, Carson RE, Kolachana BS, De Benes FM, Khan Y, Vincent SL, Wickramasinghe R (1996a). Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra Differences in the subregional and cellular distribution of AK, Eckelman WC, Pickar D (1997). Schizophrenia is GABAA receptor binding in the hippocampal formation of associated with elevated amphetamine-induced synaptic schizophrenic brain. Synapse 22, 338±349. dopamine concentrations : evidence form a novel positron Benes FM, Kwok EW, Vincent SL, Todtenkopf MS (1998). A emission tomography method. Proceedings of the National reduction of nonpyramidal cells in sector CA2 of Academy of Sciences USA 94, 2569±2574. schizophrenics and manic depressives. Biological Psychiatry Bu DF, Erlander MG, Hitz BC, Tillakaratne NJ, Kaufman DL, 44, 88±97. Wagner-McPherson CB, Evans GA, Tobin AJ (1992). Two The GABAergic system in schizophrenia 175 human glutamate decarboxylases, 65-kDa GAD and 67- Dudel J, Gryder R, Kaji A, Kuffler SW, Potter DD (1963). kDa GAD, are each encoded by a single gene. Proceedings Gamma-aminobutyric acid and other blocking compounds of the National Academy of Sciences USA 89, 2115±2119. in crustacea I. Central nervous system. Journal of Carlsson A (1988). The current status of the dopamine Neurophysiology 26, 721±728. hypothesis of schizophrenia. Neuropsychopharmacology 1, Erlander MG, Tobin AJ (1991). The structural and functional 179±186. heterogeneity of glutamic acid decarboxylase, a review. Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Neurochemical Research 16, 215±226. Carlsson ML (2001). Interactions between monoamines, Esclapez M, Tillakaratne NJK, Kaufman DL, Tobin AJ, Houser glutamate, and GABA in schizophrenia, new evidence. CR (1994). Comparative localization of two forms of Annual Review of Pharmacology and Toxicology 41, 237±260. glutamic acid decarboxylase and their mRNAs in rat brain Cheetham SC, Crompton MR, Katona CLE, Parker SJ, Horton supports the concept of functional differences between the RW (1988). Brain GABA }benzodiazepine binding sites A forms. Journal of Neuroscience 14, 1834±1855. and glutamic acid decarboxylase activity in depressed Feldblum S, Erlander MG, Tobin AJ (1993). Different suicide victims. Brain Research 460, 114±123. distributions of GAD65 and GAD67 mRNAs suggest that Conde F, Lund JS, Jacobowitz DM, Baimbridge KG, Lewis the two glutamate decarboxylases play distinctive DA (1994). Local circuit neurons immunoreactive for functional roles. Journal of Neuroscience Research 34, calretinin, calbindin D-28k or parvalbumin in monkey 689±706. prefrontal cortex : distribution and morphology. Journal of Ferkany JW, Butler IJ, Enna SJ (1979). Effect of drugs on rat Comparative Neurology 341, 95±116. brain, cerebrospinal ¯uid and blood GABA content. Journal Cross AJ, Crow TJ, Owen F (1979). Gamma-aminobutyric of Neurochemistry 33, 29±33. acid in the brain in schizophrenia. Lancet 1, 560±561. Florey E (1991). GABA : history and perspectives. Canadian Cross AJ, Owen F (1979). The activities of glutamic acid Journal of Physiology and Pharmacology 69, 1049±1056. decarboxylase and choline acetyltransferase in post-mortem Florey E, McLennan H (1955). The release of an inhibitory brains of schizophrenics and controls. Biochemical Society substance from mammalian brain and its action on Transactions 7, 145±146. peripheral synaptic transmission. Journal of Physiology Crow TJ, Owen F, Cross AJ, Lofthouse R, Longden A (1978). (London) 129, 384±392. Brain biochemistry in schizophrenia. Lancet 1, 36±37. Fuxe K, Perez de la Mora M, Ho$ kfelt T (1977). GABA±DA Curran T, D'Arcangelo G (1998). Role of reelin in the control interactions and their possible relation to schizophrenia. In : of brain development. Brain Research Brain Research Reviews Shagass C, Gershon S, Friedhoff AJ (Eds.), Psychopathology 26, 285±294. $ and Brain Pathology (pp. 97±111). New York : Raven Press. Czudek C, Reynolds GP (1990). [ H]nipecotic acid binding to Garbutt JC, van Kammen DP (1983). The interaction between gamma-aminobutyric acid uptake sites in postmortem human brain. Journal of Neurochemistry 55, 165±168. GABA and dopamine : implications for schizophrenia. Daviss SR, Lewis DA (1995). Local circuit neurons of the Schizophrenia Bulletin 9, 336±353. prefrontal cortex in schizophrenia, selective increase in the Gattaz WF, Roberts E, Beckmann H (1986). Cerebrospinal density of calbindin-immunoreactive neurons. Psychiatry ¯uid concentrations of free GABA in schizophrenia, no Research 59, 81±96. changes after haloperidol treatment. Journal of Neural Deakin JFW, Simpson MDC (1997). A two-process theory of Transmission 66, 69±73. schizophrenia, evidence from studies in post-mortem brain. Gerner RH, Fairbanks L, Anderson GM, Young JG, Scheinin Journal of Psychiatric Research 31, 277±295. M, Linnoila M, Hare TA, Shaywitz BA, Cohen DJ (1984). Dean B (2001). A predicted cortical serotonergic} CSF neurochemistry in depressed, manic, and schizophrenic cholinergic}GABAergic interface as a site of pathology patients compared with that of normal controls. American in schizophrenia. Clinical and Experimental Pharmacology Journal of Psychiatry 141, 1533±1540. and Physiology 28, 74±78. Gerner RH, Hare TA (1981). CSF GABA in normal subjects Dean B, Hussain T, Hayes W, Scarr E, Kitsoulis S, Hill C, and patients with depression, schizophrenia, mania, and Opeskin K, Copolov DL (1999). Changes in serotonin A anorexia nervosa. American Journal of Psychiatry 138, and GABA receptors in schizophrenia, studies on the 1098±1101. human dorsolateral prefrontal cortex. Journal of Gold BI, Bowers Jr. MB, Roth RH, Sweeney DW (1980). Neurochemistry 72, 1593±1599. GABA levels in CSF of patients with psychiatric disorders. Deutsch SI, Rosse RB, Schwartz BL, Mastropaolo J (2001). A American Journal of Psychiatry 137, 362±364. revised excitotoxic hypothesis of schizophrenia, therapeutic Goldman-Rakic PS (1996). Regional and cellular fractionation implications. Clinical Neuropharmacology 24, 43±49. of working memory. Proceedings of the National Academy of Dewey SL, Smith GS, Logan J, Brodie JD, Yu DW, Ferrieri Sciences USA 93, 13473±13480. RA, King PT, MacGregor RR, Martin TP, Wolf AP (1992). Grace AA (1991). Phasic versus tonic dopamine release and GABAergic inhibition of endogenous dopamine release the modulation of dopamine system responsivity, a measured in vivo with 11C-raclopride and positron hypothesis for the etiology of schizophrenia. Neuroscience emission tomography. Journal of Neuroscience 12, 41, 1±24. 3773±3780. 176 B. P. Blum and J. J. Mann Guidotti A, Auta J, Davis JM, Gerevini VD, Dwivedi Y, Kaufman DL, Houser CR, Tobin AJ (1991). Two forms of the Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma c-aminobutyric acid synthetic enzyme glutamate R, Uzunov D, Costa E (2000). Decrease in reelin and decarboxylase have distinct intraneuronal distributions and glutamic acid decarboxylase (GAD ) expression in cofactor interactions. Journal of Neurochemistry 56, 720±723. '( '( schizophrenia and bipolar disorder, a postmortem brain Keverne EB (1999). GABA-ergic neurons and the study. Archives of General Psychiatry 57, 1061±1069. neurobiology of schizophrenia and other psychoses. Brain Gupta A, Wang Y, Markram H (2000). Organizing principles Research Bulletin 48, 467±473. for a diversity of GABAergic interneurons and synapses in Kiuchi Y, Kobayashi T, Takeuchi J, Shimizu H, Ogata H, Toru the neocortex. Science 287, 273±278. M (1989). Benzodiazepine receptors increase in post- Hanada S, Mita T, Nishino N, Tanaka C (1987). [$H]muscimol mortem brain of chronic schizophrenics. European Archives binding sites increased in autopsied brains of chronic of Psychiatry and Neurological Sciences 239, 71±78. schizophrenics. Life Sciences 40, 259±266. Korpi ER, Kleinman JE, Goodman SI, Wyatt RJ (1987). Hardy JA, Dodd PR, Oakley AE, Kidd AM, Perry RH, Neurotransmitter amino acids in post-mortem brains of Edwardson JA (1982). Use of post-mortem human chronic schizophrenic patients. Psychiatry Research 22, synaptosomes for studies of metabolism and transmitter 291±301. amino acid release. Neuroscience Letters 33, 317±322. Kravitz EA, Kuffler SW, Potter DD (1963). Gamma- Hendry SHC, Fuchs J, deBlas AL, Jones EG (1990). aminobutyric acid and other blocking compounds in Distribution and plasticity of immunocytochemically crustaceans. III. Their relative concentrations in separated localized GABA receptors in adult monkey cortex. Journal motor and inhibitory axons. Journal of Neurophysiology 26, of Neuroscience 10, 2438±2450. 739±751. Hendry SHC, Huntsman MM, Vin4 uela A, Mo$ hler H, de Blas Kutay FZ, Po$ gu$ nST , Hariri NI, Peker G, Erlac: in S (1989). Free AL, Jones EG (1994). GABA receptor subunit amino acid level determinations in normal and immunoreactivity in primate visual cortex, distribution in schizophrenic brain. Progress in Neuro-Psychopharmacology macaque and humans and regulation by visual input in and Biological Psychiatry 13, 119±126. adults. Journal of Neuroscience 14, 2383±2401. Lewis DA, Pierri JN, Volk DW, Melchitzky DS, Woo TU Holstein GR, Pasik P, Hamori J (1986). Synapses between (1999). Altered GABA neurotransmission and prefrontal GABA-immunoreactive axonal and dendritic elements in cortical dysfunction in schizophrenia. Biological Psychiatry monkey substantia nigra. Neuroscience Letters 66, 316±322. 46, 616±626. Huffman RD, Ticku MK (1983). The effects of chronic Lewis DA (2000). GABAergic local circuit neurons and haloperidol administration on GABA receptor binding. prefrontal cortical dysfunction in schizophrenia. Brain Pharmacology, Biochemistry and Behavior 19, 199±204. Research Brain Research Reviews 31, 270±276. Huntsman MM, Isackson PJ, Jones EG (1994). Lamina-speci®c Lichtshtein D, Dobkin J, Ebstein RP, Biederman J, Rimon R, expression and activity-dependent regulation of seven Belmaker RH (1978). Gamma-aminobutyric acid (GABA) in GABA receptor subunit mRNA in monkey visual cortex. the CSF of schizophrenic patients before and after Journal of Neuroscience 14, 2236±2259. neuroleptic treatment. British Journal of Psychiatry 132, Huntsman MM, Tran BV, Potkin SG, Bunney Jr. WE, Jones 145±148. EG (1998). Altered ratios of alternatively spliced long and Lund JS, Lewis DA (1993). Local circuit neurons of short c2 subunit mRNAs of the c-amino butyrate type A developing and mature macaque prefrontal cortex, Golgi receptor in prefrontal cortex of schizophrenics. Proceedings and immunocytochemical characteristics. Journal of of the National Academy of Sciences USA 95, 15066±15071. Comparative Neurology 328, 282±312. Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho Luntz-Leybman V, Rotter A, Zdilar D, Frostholm A (1995). H, Pisu MG, Uzunov DP, Smalheiser NR, Davis JM, Uncoupling of GABA }benzodiazepine receptor a , b , " # Pandey GN, Pappas GD, Tueting P, Sharma RP, Costa E and c subunit mRNA expression in cerebellar Purkinje (1998). A decrease of reelin expression as a putative cells of staggerer mutant mice. Journal of Neuroscience 15, vulnerability factor in schizophrenia. Proceedings of the 8121±8130. National Academy of Sciences USA 95, 15718±15723. Manchon M, Kopp N, Rouzioux JJ, Lecestre D, Deluermoz S, Japha K, Koch M (1999). Picrotoxin in the medial prefrontal Miachon S (1987). Benzodiazepine receptor and cortex impairs sensorimotor gating in rats, reversal by neurotransmitter studies in the brain of suicides. Life haloperidol. Psychopharmacology 144, 347±354. Sciences 41, 2623±2630. Jones EG (1990). GABA-peptide neurons in the neocortex McCarthy BW, Gomes UR, Neethling AC, Shanley BC, (` Inhibition in the Brain ' Symposium, November 1986, Taljaard JJ, Potgieter L, Roux JT (1981). c-aminobutyric Washington, DC). In: Paxinos G (Ed.), The Human Brain (p. acid concentration in cerebrospinal ¯uid in schizophrenia. 1116). San Diego : Academic Press. Journal of Neurochemistry 36, 1406±1408. Kalus P, Senitz D, Beckmann H (1997). Altered distribution of McGeer PL, McGeer EG (1976). Enzymes associated with the parvalbumin-immunoreactive local circuit neurons in the metabolism of catecholamines, acetylcholine and GABA in anterior cingulate cortex of schizophrenic patients. human controls and patients with Parkinson's disease and Psychiatry Research, Neuroimaging Section 75, 49±59. Huntington's chorea. Journal of Neurochemistry 26, 65±76. The GABAergic system in schizophrenia 177 McGeer PL, McGeer EG (1977). Possible changes in striatal Perry TL, Hansen S, Gandham SS (1981). Postmortem and limbic cholinergic systems in schizophrenia. Archives of changes of amino compounds in human and rat brain. General Psychiatry 34, 1319±1323. Journal of Neurochemistry 36, 406±412. McGeer PL, McGeer EG, Wada JA (1971). Glutamic acid Perry TL, Hansen S, Jones K (1989). Schizophrenia, tardive decarboxylase in Parkinson's disease and epilepsy. dyskinesia, and brain GABA. Biological Psychiatry 25, Neurology 21, 1000±1007. 200±206. Mizukami K, Sasaki M, Ishikawa M, Iwakiri M, Hidaka S, Perry TL, Kish SJ, Buchanan J, Hansen S (1979). c- Shiraishi H, Iritani S (2000). Immunohistochemical aminobutyric-acid de®ciency in brain of schizophrenic localization of c-aminobutyric acid receptor in the patients. Lancet 1, 237±239. hippocampus of subjects with schizophrenia. Neuroscience Petty F, Sherman AD (1984). Plasma GABA levels in Letters 283, 101±104. psychiatric illness. Journal of Affective Disorders 6, 131±138. Mo$ hler H, Benke D, Fritschy JM, Benson J (2000). The Pierri JN, Chaudry AS, Woo TU, Lewis DA (1999). benzodiazepine site of GABA receptors. In : Martin D, Alterations in chandelier neuron axon terminals in the Olsen R (Eds.), GABA in the Nervous System, The View at prefrontal cortex of schizophrenic subjects. American Journal Fifty Years (pp. 97±112). Philadelphia : Lippincott Williams of Psychiatry 156, 1709±1719. & Wilkins. Reveley MA, Gurling HMD, Glass I, Glover V, Sandler M Moore H, West AR, Grace AA (1999). The regulation of (1980). Platelet c-aminobutyric acid-aminotransferase and forebrain dopamine transmission, relevance to the monoamine oxidase in schizophrenia. Neuropharmacology pathophysiology and psychopathology of schizophrenia. 19, 1249±1250. Biological Psychiatry 46, 40±55. Reynolds GP, Beasley CL (2001). GABAergic neuronal Muly III EC, Szigeti K, Goldman-Rakic PS (1998). D1 receptor subtypes in the human frontal cortex ± development and in interneurons of Macaque prefrontal cortex, distribution de®cits in schizophrenia. Journal of Chemical Neuroanatomy and subcellular distribution. Journal of Neuroscience 18, 22, 95±100. 10553±10565. Reynolds GP, Czudek C, Andrews HB (1990). De®cit and Ohnuma T, Augood SJ, Arai H, McKenna PJ, Emson PC hemispheric asymmetry of GABA uptake sites in the (1999). Measurement of GABAergic parameters in the hippocampus in schizophrenia. Biological Psychiatry 27, prefrontal cortex in schizophrenia, focus on GABA content, 1038±1044. GABA receptor a-1 subunit messenger RNA and human Reynolds GP, Stroud D (1993). Hippocampal benzodiazepine GABA transporter-1 (HGAT-1) messenger RNA receptors in schizophrenia. Journal of Neural Transmission expression. Neuroscience 93, 441±448. (General Section) 93, 151±155. Okada Y, Nitsch-Hassler C, Kim JS, Bak IJ, Hassler R (1971). Rimvall K, Martin DL (1994). The level of GAD67 protein is Role of c-aminobutyric acid (GABA) in the extrapyramidal highly sensitive to small increases in intraneuronal gamma- motor system. 1. Regional distribution of GABA in rabbit, aminobutyric acid levels. Journal of Neurochemistry 62, rat, guinea pig and baboon CNS. Experimental Brain 1375±1381. Research 13, 514±518. Rimvall K, Sheikh SN, Martin DL (1993). Effects of increased Olney JW, Farber NB (1995). Glutamate receptor dysfunction gamma-aminobutyric acid levels on GAD67 protein and and schizophrenia. Archives of General Psychiatry 52, mRNA levels in rat cerebral cortex. Journal of 998±1007. Neurochemistry 60, 714±720. Olsen R, Homanics G (2000). Function of GABA receptors ; Roberts E (1972). An hypothesis suggesting that there is a insights from mutant and knockout mice. In : Martin D, defect in the GABA system in schizophrenia. Neurosciences Olsen R (Eds.), GABA in the Nervous System, The View at Research Program Bulletin 10, 468±481. Fifty Years (pp. 81±96). Philadelphia : Lippincott Williams & Roberts E, Frankel S (1950). c-aminobutyric acid in brain, its Wilkins. formation from glutamic acid. Journal of Biological Chemistry Orkand PM, Kravitz EA (1971). Localization of the sites of c- 187, 55±63. aminobutyric acid (GABA) uptake in lobster nerve-muscle Rochet T, Kopp N, Vedrinne J, Deluermoz S, Debilly G, preparations. Journal of Cell Biology 49, 75±89. Miachon S (1992). Benzodiazepine binding sites and their Otsuka M, Iversen LL, Hall ZW, Kravitz EA (1966). Release modulators in hippocampus of violent suicide victims. of gamma-aminobutyric acid from inhibitory nerves of Biological Psychiatry 32, 922±931. lobster. Proceedings of the National Academy of Sciences USA Schiffer WK, Gerasimov M, Hofmann L, Marsteller D, Ashby 56, 1110±1115. CR, Brodie JD, Alexoff DL, Dewey SL (2001). Gamma Pandey GN, Conley RR, Pandey SC, Goel S, Roberts RC, vinyl-GABA differentially modulates NMDA antagonist- Tamminga CA, Chute D, Smialek J (1997). Benzodiazepine induced increases in mesocortical versus mesolimbic DA receptors in the post-mortem brain of suicide victims and transmission. Neuropsychopharmacology 25, 704±712. schizophrenic subjects. Psychiatry Research 71, 137±149. Schlander M, Thomalske G, Frotscher M (1987). Fine Perry EK, Blessed G, Perry RH, Tomlinson BE (1978). Brain structure of GABAergic neurons and synapses in the biochemistry in schizophrenia. Lancet 1, 35±36. human dentate gyrus. Brain Research 401, 185±189. 178 B. P. Blum and J. J. Mann Spokes EG (1980). Neurochemical alterations in Huntington's Sesack SR, Hawrylak VA, Melchitzky DS, Lewis DA (1998). Dopamine innervation of a subclass of local circuit neurons chorea, a study of post-mortem brain tissue. Brain 103, in monkey prefrontal cortex : ultrastructural analysis of 179±210. tyrosine hydroxylase and parvalbumin immunoreactive Spokes EGS, Garrett NJ, Iversen LL (1979). Differential effects structures. Cerebral Cortex 8, 614±622. of agonal status on measurements of GABA and glutamate Sesack SR, Snyder CL, Lewis DA (1995). Axon terminals decarboxylase in human post-mortem brain tissue from immunolabeled for dopamine or tyrosine hydroxylase control and Huntington's chorea subjects. Journal of synapse on GABA-immunoreactive dendrites in rat and Neurochemistry 33, 773±778. monkey cortex. Journal of Comparative Neurology 363, Spokes EGS, Garrett NJ, Rossor MN, Iversen LL (1980). 264±280. Distribution of GABA in post-mortem brain tissue from Sheikh SN, Martin DL (1998). Elevation of brain GABA levels control, psychotic and Huntington's chorea subjects. Journal with vigabatrin (gamma-vinylGABA) differentially affects of the Neurological Sciences 48, 303±313. GAD65 and GAD67 expression in various regions of rat Squires RF, Lajtha A, Saederup E, Palkovits M (1993). brain. Journal of Neuroscience Research 52, 736±741. Reduced [$H]¯unitrazepam binding in cingulate cortex and Sheikh SN, Martin SB, Martin DL (1999). Regional hippocampus of postmortem schizophrenic brains : is distribution and relative amounts of glutamate selective loss of glutamatergic neurons associated with decarboxylase isoforms in rat and mouse brain. major psychoses? Neurochemical Research 18, 219±223. Neurochemistry International 35, 73±80. Squires RF, Saederup E (1991). A review of evidence for Sherif F, Eriksson L, Oreland L (1992). Gamma-aminobutyrate GABergic predominance}glutamatergic de®cit as a aminotransferase activity in brains of schizophrenic common etiological factor in both schizophrenia and patients. Journal of Neural Transmission (General Section) 90, affective psychoses, more support for a continuum 231±240. hypothesis of ` functional ' psychosis. Neurochemical Research Sherman AD, Davidson AT, Baruah S, Hegwood TS, Waziri 16, 1099±1111. R (1991). Evidence of glutamatergic de®ciency in Sternberg DE (1980). CSF c-aminobutyric acid (GABA) in schizophrenia. Neuroscience Letters 121, 77±80. schizophrenia, Proceedings of the 133rd American Psychiatric Simpson MDC, Royston MC, Slater P, Deakin JFW (1992a). Association, pp. 80±81. Neurochemical abnormalities of the cerebral cortex in Stevens J, Wilson K, Foote W (1974). GABA blockade, schizophrenia. Schizophrenia Research 6, 133±134. dopamine and schizophrenia, experimental studies in the Simpson MDC, Slater P, Deakin JFW (1998a). Comparison of cat. Psychopharmacologia (Berlin) 39, 105±119. glutamate and gamma-aminobutyric acid uptake binding Stevens JR (1999). Epilepsy, schizophrenia, and the extended sites in frontal and temporal lobes in schizophrenia. amygdala. Annals of the New York Academy of Sciences 877, Biological Psychiatry 44, 423±427. Simpson MDC, Slater P, Deak JFW, Gottfries CG, Karlsson I, 548±561. Grenfeldt B, Crow TJ (1998b). Absence of basal ganglia Stocks GM, Cheetham SC, Crompton MR, Katona CL, amino acid neuron de®cits in schizophrenia in three Horton RW (1990). Benzodiazepine binding sites in collections of brains. Schizophrenia Research 31, 167±175. amygdala and hippocampus of depressed suicide victims. Simpson MDC, Slater P, Deakin JFW, Royston MC, Skan WJ Journal of Affective Disorders 18, 11±15. (1989). Reduced GABA uptake sites in the temporal lobe in Stone DJ, Walsh J, Benes FM (1999). Localization of cells schizophrenia. Neuroscience Letter 107, 211±215. preferentially expressing GAD(67) with negligible Simpson MDC, Slater P, Royston MC, Deakin JFW (1992b). GAD(65) transcripts in the rat hippocampus. A double in Regionally selective de®cits in uptake sites for glutamate situ hybridization study. Brain Research Molecular Brain and gamma-aminobutyric acid in the basal ganglia in Research 71, 201±209. schizophrenia. Psychiatry Research 42, 273±282. Todtenkopf MS, Benes FM (1998). Distribution of glutamate Smith Y, Parent A, Seguela P, Descarries L (1987a). decarboxylase immunoreactive puncta on pyramidal and '& Distribution of GABA-immunoreactive neurons in the basal nonpyramidal neurons in hippocampus of schizophrenic ganglia of the squirrel monkey (Saimiri sciureus). Journal of brain. Synapse 29, 323±332. Comparative Neurology 259, 50±64. Toru M, Watanabe S, Shibuya H, Nishikawa T, Noda K, Smith Y, Seguela P, Parent A (1987b). Distribution of GABA- Mitsushio H, Ichikawa H, Kurumaji A, Takashima M, immunoreactive neurons in the thalamus of the squirrel Mataga N, Ogawa A (1988). Neurotransmitters, receptors monkey (Saimiri sciureus). Neuroscience 22, 579±591. and neuropeptides in post-mortem brains of chronic Sorvari H, Soininen H, Paljarvi L, Karkola K, Pitkanen A schizophrenic patients. Acta Psychiatrica Scandinavica 78, (1995). Distribution of parvalbumin-immunoreactive cells 121±137. and ®bers in the human amygdaloid complex. Journal of Udenfriend S (1950). Identi®cation of c-aminobutyric acid in Comparative Neurology 360, 185±212. brain by the isotope derivative method. Journal of Biological Spokes EGS (1979). An analysis of factors in¯uencing Chemistry 187, 65±69. measurements of dopamine, noradrenaline, glutamate van Kammen DP (1979). The dopamine hypothesis of decarboxylase and choline acetylase in human post-mortem schizophrenia revisited. Psychoneuroendocrinology 4, 37±46. brain tissue. Brain 102, 333±346. The GABAergic system in schizophrenia 179 van Kammen DP, Petty F, Kelley ME, Kramer GL, Barry EJ, III WJ, Rose RM (1999). Critical review of GABA-ergic Yao JK, Gurklis JA, Peters JL (1998). GABA and brain drugs in the treatment of schizophrenia. Journal of Clinical abnormalities in schizophrenia. Psychiatry Research, Psychopharmacology 19, 222±232. Neuroimaging Section 82, 25±35. White HL, Davidson JR, Miller RD, Faison LD (1980). Platelet van Kammen DP, Sternberg DE, Hare TA, Waters RN, c-aminobutyrate-a-ketoglutarate transaminase (GABA-T) in Bunney Jr. WE (1982). CSF levels of c-aminobutyric acid in schizophrenia. American Journal of Psychiatry 137, 733±734. schizophrenia. Low values in recently ill patients. Archives Woo TU, Miller JL, Lewis DA (1997). Schizophrenia and the of General Psychiatry 39, 91±97. parvalbumin-containing class of cortical local circuit Vincent SL, Adamec E, Sorensen I, Benes FM (1994). The neurons. American Journal of Psychiatry 154, 1013±1015. effects of chronic haloperidol administration on GABA- Woo TU, Whitehead RE, Melchitzky DS, Lewis DA (1998). A immunoreactive axon terminals in rat medial prefrontal subclass of prefrontal c-aminobutyric acid axon terminals cortex. Synapse 17, 26±35. are selectively altered in schizophrenia. Proceedings of the Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA National Academy of Sciences USA 95, 5341±5346. (2000). Decreased glutamic acid decarboxylase messenger Zander KJ, Fischer B, Zimmer R, Ackenheil M (1981). Long- '( RNA expression in a subset of prefrontal cortical c- term neuroleptic treatment of chronic schizophrenic aminobutyric acid neurons in subjects with schizophrenia. patients, clinical and biochemical effects of withdrawal. Archives of General Psychiatry 57, 237±245. Psychopharmacology 73, 43±47. Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA Zimmer R, Teelken AW, Meier KD, Ackenheil M, Zander KJ (2001). GABA transporter-1 mRNA in the prefrontal cortex (1981). Preliminary studies on CSF gamma-aminobutyric in schizophrenia, decreased expression in a subset of acid levels in psychiatric patients before and during neurons. American Journal of Psychiatry 158, 256±265. treatment with different psychotropic drugs. Progress in Wassef AA, Dott SG, Harris A, Brown A, O'Boyle M, Meyer Neuro-Psychopharmacology 4, 613±620. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Neuropsychopharmacology Oxford University Press

The GABAergic system in schizophrenia

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Oxford University Press
Copyright
© 2002 Collegium Internationale Neuropsychopharmacologicum
ISSN
1461-1457
eISSN
1469-5111
DOI
10.1017/S1461145702002894
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See Article on Publisher Site

Abstract

A defect in neurotransmission involving c-amino butyric acid (GABA) in schizophrenia was ®rst proposed in the early 1970s. Since that time, a considerable effort has been made to ®nd such a defect in components of the GABAergic system. After a brief introduction focusing on historical perspectives, this paper reviews post- mortem and other biological studies examining the following components of the GABAergic system in schizophrenic subjects : the GABA biosynthetic enzyme, glutamate decarboxylase ; free GABA ; the GABA transporter ; the GABA , GABA and benzodiazepine receptors ; and the catabolic enzyme GABA A B transaminase. Additionally, post-mortem studies using morphology or calcium-binding protein to identify GABAergic neurons are also reviewed. Substantial evidence argues for a defect in the GABAergic system of the frontal cortex in schizophrenia which is limited to the parvalbumin-class of GABAergic interneurons. Received 18 July 2001 ; Reviewed 11 November 2001 ; Revised 28 January 2002 ; Accepted 30 January 2002 Key words : CSF, GABA, post-mortem, schizophrenia. Historical perspectives use GABA in neurotransmission (Bloom and Iversen, 1971). In the monkey cortex approx. 25 % of the neurons The physiologists Ernst and Friedrich Weber (1845), Ivan in most regions are GABAergic ( Jones, 1990). In addition Pavlov (1885) and Wilhelm Biedermann (1887) estab- to the neocortex, signi®cant populations of glutamate lished the concept of inhibition in the nervous system and decarboxylase (GAD)- or GABA-immunoreactive (IR) cell lead to the identi®cation of inhibitory neurons by Cornelis bodies or axon terminals have also been identi®ed in Wiersma (1933) (Florey, 1991). Roberts and Frankel primate brain regions including the midbrain (Holstein et (1950), Awapara et al. (1950), and Udenfriend (1950) al., 1986 ; Okada et al., 1971), hippocampal formation reported the isolation of c-aminobutyric acid (GABA) (Schlander et al., 1987), the thalamus (Smith et al., 1987b), from animal brain material. Working on cray®sh stretch the basal ganglia (Smith et al., 1987a), and the amygdala receptors initially and later with the monosynaptic knee- (Sorvari et al., 1995). jerk re¯ex in cats, Ernst Florey reported that a Factor I had GABA was ®rst implicated in the pathophysiology of inhibitory effects in these systems (Florey and McLennan, schizophrenia by Eugene Roberts in 1972. He proposed 1955). Factor I was later puri®ed from beef brain and that a susceptibility to schizophrenia might be due to a shown to be identical to GABA (Bazemore et al., 1957). defect in the inhibitory GABAergic neurons control of The status of GABA as neurotransmitter was not widely neural circuits governing behavioral responses. This accepted until further studies in crustaceans established defect would be exacerbated under stressful conditions in that GABA was the most common inhibitory substance in which increased monoaminergic drive would increase the CNS (Dudel, 1963), that peripheral inhibitory but not disinhibitory input onto those GABA neurons, producing excitatory neurons contained high GABA concentrations abnormalities of perceptual and cognitive integration (Kravitz et al., 1963), that inhibitory motor neurons (Roberts, 1972). Since this initial proposal, a role for released GABA (Otsuka et al., 1966), and that GABA is GABA in the pathophysiology of schizophrenia continues removed from the postsynaptic cleft by an uptake process to be formulated in the context of complex interactions (Orkand and Kravitz, 1971). between GABA and other neurotransmitter systems. GABA is the major inhibitory neurotransmitter in the Carlsson (1988) proposed a model of psychosis that mammalian brain ; up to 30 % of cortical neurons in rats involves multiple neurotransmitters including a defective GABA-mediated inhibition of glutamatergic feedback Address for correspondence : Dr B. P. Blum, New York State inhibition of mesolimbic dopamine function and describes Psychiatric Institute, Department of Neuroscience, 1051 Riverside a defect in thalamic ®ltering of sensory and arousal input Drive, Unit 42, New York, NY, 10032, USA. to the cortex (see also Carlsson et al., 2001). An Tel. : 212-543-6223 Fax : 212-543-6017 abnormality in GABAergic regulation of dopamine cell E-mail : bb453!columbia.edu 160 B. P. Blum and J. J. Mann burst ®ring has been postulated to underlie the symptoms agents have generally not been demonstrated to produce of schizophrenia (Grace, 1991 ; Moore et al., 1999). antipsychotic effects in of themselves (Wassef et al., Others have noted, in the direct modulation of the 1999). In-vivo pharmacological manipulation of the dopaminergic system by GABAergic neurons, a potential GABAergic system indicates that GABAergic function is mechanism whereby an abnormality in the GABAergic potentially relevant to the pathophysiology of schizo- system could be involved in the dopaminergic dys- phrenia. For example, blockade of GABA receptors with function of schizophrenia (Carlsson, 1988 ; Fuxe et al., picrotoxin in the prefrontal cortex of rats impairs 1977 ; Garbutt and van Kammen, 1983 ; Stevens et al., sensorimotor gating, an effect that is reversed by 1974 ; van Kammen, 1979). Squires and Saederup (1991) haloperidol (Japha and Koch, 1999). Conversely, en- postulated that schizophrenia involved a GABAergic hancement of GABAergic activity by either c-vinyl- predominance caused by either hyperactive GABA GABA (GVG) or lorazepam in baboons inhibits dopamine receptors or hypoactive glutamate receptors and}or transmission in the striatum as indicated by increased destruction of counterbalancing glutamatergic neurons by [""C]raclopride binding (Dewey et al., 1992). Furthermore, neurotropic pathogens. This last model has received little GVG treatment has been shown to increases phencycli- ongoing support. dine-induced release of dopamine in a dose-dependent Olney and Farber (1995) developed a model of manner in the rat prefrontal cortex but not in the striatum schizophrenia in which a state of ` NMDA receptor (Schiffer et al., 2001). Hypofunctioning of the GABAergic hypofunction ' is caused by either intrinsically hypofunc- system may be responsible for the striatal dopamine tioning NMDA receptors or through excitotoxic loss of overactivity and behavioural changes noted in schizo- NMDA receptor-bearing GABAergic neurons. This state phrenic subjects (Breier et al., 1997). results in excessive dopaminergic input into corticolimbic The purpose of this paper is to review the data regions (also see Carlsson et al., 2001) with resultant from post-mortem and other biological studies of the further hypofunctioning of the glutamatergic system GABAergic system in schizophrenia in order to provide a through feedback mechanisms. Several classes of com- synthesis of what is known. pounds, including benzodiazepines (BZD), muscurinic receptor antagonist and haloperidol, blocked NMDA- induced neurotoxicity in the posterior cingulate and GAD retrospenial regions of experimental animals. Loss of GABAergic interneurons in the hippocampal formation, GAD, the rate-limiting biosynthetic enzyme of GABA, possible secondary to excitotoxic injury (Benes, 1999) or catalyses the decarboxylation of glutamic acid to yield to loss of glutamatergic neurons has also been hypo- GABA. Two major isoenzymes of GAD, named GAD '& thesized (Deakin and Simpson, 1997). Similarly, Deutsch and GAD , based on their approximate molecular weight '( et al. (2001) postulates a failure of GABAergic inhibition of 65±4 and 66±6 kDa respectively, have been identi®ed in of the AMPA}kainite class of glutamatergic receptor with human brain (Bu et al., 1992). GAD is preferentially '& a resultant cascade of excitotoxic events. localized in axon terminals (Esclapez et al., 1994), more A dysfunction of a7-nicotinic acetylcholine receptor tightly membrane associated and more often exists in an on GABA interneurons in the hippocampus (Adler et al., inactive apoGAD form (lacking the cofactor pyridoxal 1998) or disruption of interactions between the choliner- phosphate) compared with the GAD isoenzyme (Kauf- '( gic system and 5-HT receptor on GABAergic inter- man et al., 1991). In rat hippocampus, most cells express neurons in the frontal cortex (Dean, 2001) has been transcripts of both GAD isoenzymes (Stone et al., 1999). proposed as sites of pathophysiology in schizophrenia. It has been suggested that GAD might preferentially '& Relationships between epilepsy, schizophrenia and the synthesize GABA for vesicular release and that GAD '( GABAergic system have been proposed (Keverne, 1999 ; may be preferentially involved in synthesis of cytoplasmic Stevens, 1999). Effects of the GABAergic system in GABA (Erlander and Tobin 1991 ; Esclapez et al., 1994 ; neuro- and in particular cortico-developmental processes Feldblum et al., 1993). have been integrated into developmental hypotheses of Early efforts to detect an abnormality in the GABAergic psychosis and schizophrenia. GABAergic interneurons system focused on determining activity levels of GAD. form the substrate for the gamma frequency oscillations Seven such studies were performed on cortical tissue postulated to synchronize brain activity in disparate homogenates from parts of the temporal and frontal regions of the brain and an abnormality in such may cause lobes : all but two of which reported no signi®cant psychosis (for a review see Keverne, 1999). difference between controls and patients with schizo- Although there is some evidence for a role for BZD and phrenia in these regions (see Table 1a) (Bennett et al., valproate in the treatment of schizophrenia, GABAergic 1979 ; Bird et al., 1977 ; Cross and Owen, 1979 ; Crow et The GABAergic system in schizophrenia 161 Table 1a. GABAergic presynaptic markers in schizophrenia Marker Area Finding Comment Author GAD activity Hippocampus 5 McGeer and McGeer (1977) BA 11, 37, 38 5 BA 7 i 35 %* BA 18 i 43 %* BA 34 i 39 %* GAD activity Hippocampus i 48±2 %* Bird et al. (1977) N. accumbens i 44 %* Putamen i 27 %* Amygdala i 46 %* GAD activity Hippocampus 5 Perry et al. (1978) BA 21 5 BA 10 5 GAD activity Frontal cortex 5 Found i GAD Crow et al. (1978) with j PMI GAD activity Frontal cortex 5 Cross and Owen (1979) Amygdala 5 GAD activity Multiple brain regions 5 Spokes (1980) GAD activity Frontal cortex 5 Bennett et al. (1979) GAD activity BA 9 5 Hanada et al. (1987) GAD mRNA BA 9 i 40 %* Layer I Akbarian et al. (1995b) '( i 48 %* Layer II i 30 %* Layers III±V GAD }b-actin BA 22 i 70 %* Impagnatiello et al. (1998) '( immunoreactivity GAD }b-actin BA 22 i ns '& immunoreactivity GAD mRNA-positive BA 9 i 25±35 %* Layers III±V Volk et al. (2000) '( neuron densities Ratio of GAD BA 9 i 68 %* n ¯ 6 Guidotti et al. (2000) '( mRNA to neuron-speci®c enolase mRNA level GAD protein level BA 9 i 54 %* n ¯ 15 '( GAD protein level BA 9 5 n ¯ 15 '& GAD -IR puncta Hippocampus 5 Todtenkopf and Benes (1998) '& GAD -IR puncta BA 10 5 Benes et al. (2000) '& BA 24 5 * Indicates ®ndings reported as signi®cant by original authors (and throughout all tables). ns, not signi®cant. al., 1978 ; McGeer and McGeer, 1977 ; Perry et al., 1978 ; as comorbidity, medication and smoking history, diag- Spokes, 1980). One of the divergent studies found nostic heterogeneity and cause-of-death effects were signi®cantly lower GAD activity in the sensory as- not clearly addressed. Although some studies have sociation, calcarine ®ssure and insular cortex in the indicated that GAD is stable in human brain during schizophrenic group compared with controls but not in routine post-mortem handling (Spokes, 1979 ; Spokes et many other cortical and subcortical regions (McGeer and al., 1979), Crow et al. (1978) found a signi®cant negative McGeer, 1977). The second divergent study found correlation between GAD activity levels and PMI. signi®cantly lower GAD activity in patients with schizo- Although GAD activity levels is signi®cantly decreased in phrenia in all areas examined : amygdala, hippocampus, brain material obtained from patients dying of protracted nucleus accumbens, and putamen (Bird et al., 1977). illness (McGeer et al., 1971 ; McGeer and McGeer 1976 ; Whereas post-mortem interval (PMI) and age were Spokes 1979 ; Spokes et al., 1979), most of the studies controlled for in this study, other possible confounds such mentioned above did not control for this potential effect. 162 B. P. Blum and J. J. Mann A later study of GAD activity in frontal cortex [Brodmann mRNA-labelled neurons in cortical layers III±V was found area (BA) 9] and caudate from chronic schizophrenics also in the schizophrenic group compared with the controls. revealed no abnormality (Hanada et al., 1987). This study However, mean grain density per neuron did not also reported lower GAD activity in the subgroup of signi®cantly differ across the two groups. Additionally controls that had died after a prolonged terminal illness comparison of chronic haloperidol- and benztropine (PTI). The control and chronic schizophrenic group were mesylate-treated Cynomolgus monkeys with untreated fairly well matched for age, length of PMI and sex ratios. controls indicated that this medication treatment does not Before interpreting studies examining GAD gene affect GAD mRNA expression. '( expression by in-situ hybridization, it is important to note Reelin is a protein which regulates cortical cell that GAD protein levels may not match GAD mRNA positioning and}or movement during development and levels because of a variety of transcriptional, translational which appears to be expressed preferentially in and post-translational modi®cations. For example, in- GABAergic interneurons in the adult human neocortex creases in GABA levels decreases GAD activity but (Curran and D 'Arcangelo, 1998 ; Impagnatiello et al., '( does not alter GAD mRNA levels nor GAD activity 1998). Reelin protein and mRNA levels were found to be '( '& in rats (Rimvall et al., 1993 ; Rimvall and Martin, 1994). 40±50 % lower in schizophrenic subjects compared with Also, elevation of GABA by vigabatrin treatment affects controls in the prefrontal cortex (BA 10 and BA 46), GAD protein levels differently in various brain regions temporal cortex (BA 22), hippocampus, caudate and '( of the rat (Sheikh and Martin, 1998). cerebellum (Impagnatiello et al., 1998). This study also A study measured GAD mRNA in human prefrontal reported signi®cantly (E 70 %) lower GAD }b-actin but '( '( cortex by in-situ hybridization in order to determine if a not GAD }b-actin IR optical densities in the schizo- '& postulated decrease in GABA in this region was due phrenic subjects compared with controls. either to decreased gene expression or to a decrease in the A recent study measured GAD , GAD , and reelin '& '( number of GABAergic cells (Akbarian et al., 1995b). Ten mRNA levels by quantitative reverse transcriptase- schizophrenic subjects were compared to ten age, gender polymerase chain reaction and GAD and GAD protein '& '( and autolysis-time matched controls. Subjects with in- levels in brains from schizophrenic, bipolar and depressed complete medical records, substance abuse histories or subjects. Reelin mRNA, GAD protein and mRNA were '( prolonged agonal states were excluded. Fewer GAD signi®cantly lower in the prefrontal cortex and cerebellum '( mRNA-expressing neurons with no signi®cant overall in schizophrenic and psychotic bipolar but not in unipolar loss of neurons were found in cortical layers I±V of the depressed subjects without psychosis compared to normal schizophrenic subjects compared with controls. The controls (Guidotti et al., 2000). GAD mRNA levels did '& GAD mRNA levels, as measured by optical densities of not differ across the diagnostic groups. Reelin and GAD '( '( ®lm autoradiographs, were signi®cantly lower in cortical levels were found to be unrelated to PMI or neuroleptic layers II, III, IV and V of the schizophrenic subjects treatment history. compared with controls. The authors expressed doubt The distribution of GAD -immunoreactive (GAD - '& '& that the lower mRNA levels of the schizophrenic subjects IR) puncta in the hippocampus was examined in a group were secondary to neuroleptic treatment by noting that of 13 schizophrenic subjects and 13 age-, gender- and the single neuroleptic-naive schizophrenic subject had the PMI-matched controls (Todtenkopf and Benes, 1998). No lowest mRNA values. signi®cant difference was found in the density of GAD - '& A second study examined GAD mRNA expression in IR puncta in contact with pyramidal or non-pyramidal '( the prefrontal cortex of 10 schizophrenic subjects and 10 cells or dispersed within the neuropil of the layers CA1±4. sex-matched controls (Volk et al., 2000). The schizo- However, a signi®cant positive correlation was found phrenic group did not signi®cantly differ from the control between the density of GAD -IR puncta in contact with '& group with respect to age, PMI, brain pH or storage time. pyramidal and non-pyramidal cells and neuroleptic ex- One control and four schizophrenic subjects had lifetime posure in the schizophrenic subjects. This ®nding and the diagnoses of alcohol or other substance abuse and one fact that the two neuroleptic-naive schizophrenic subjects control subject had a lifetime diagnosis of depressive had the lowest density of GAD -IR puncta led the '& disorder not otherwise speci®ed. Seven schizophrenic and authors to speculate that schizophrenics might inherently nine control subjects had sudden deaths occurring outside have lowered density of GABAergic terminals in certain of a hospital ; one schizophrenic subject was a suicide regions of the hippocampus. victim. This study used in-situ hybridization followed by The density of GAD -IR terminals in layers II±VI of '& counts of silver grains within neuronal soma from the cingulate and prefrontal cortices did not differ between randomly selected cortical sites within speci®c laminar the groups (Todtenkopf and Benes, 1998) ; however, the levels. Signi®cantly (25±35 %) lower density of GAD density of GAD -IR terminals was signi®cantly lower in '( '& The GABAergic system in schizophrenia 163 layers II±IV of ®ve bipolar subjects (added in this study) section above) examined multiple cortical and subcortical compared with the normal controls (Benes et al., 2000). regions and noted lower levels only in the posterior Overall, neuroleptic treatment history did not appear to portion of the hippocampus of the schizophrenic group. correlate with terminal densities in the schizophrenic Spokes et al. (1980) found lower GABA concentrations in group. A two-dimensional counting method was used. the nucleus accumbens and the amygdala of the schizo- Three studies report lower GAD mRNA expression phrenic group compared with the controls. Absolute '( and two studies report lower GAD protein levels GABA levels in this study were in agreement with a study '( indicating that schizophrenia may be associated with less by Cross et al. (1979) but tended to be an order of GAD gene expression in the prefrontal cortex. Total magnitude higher than the other studies. In contrast to the '( GAD activity and GAD -immunoreactivity do not study of Perry et al. (1979), Cross and colleagues found no '& appear to be altered in schizophrenia. However, it should difference in GABA levels in the nucleus accumbens and be noted that the amount of GAD protein is 3- to 8-fold thalamus between the study groups. Ohnuma et al. '& greater than the amount of GAD protein in most rat (1999), using a more speci®c brain region de®nition than '( brain regions (Sheikh et al., 1999). One possibility is that the studies of Korpi et al. (1987), Perry et al. (1989), or the abnormality in schizophrenia is restricted to GAD Kutay et al. (1989), reported lower GABA levels in BA 9 '( and is not detectable by measurement of total GAD and 10, but not 11. The PMI was longer in the control enzyme activity. Moreover, there is evidence that the group than in the six schizophrenic subjects and possible GAD de®cit is limited to subset of neurons in the group sex and medication effects were not ruled out. '( prefrontal cortex (Volk et al., 2000). Nevertheless, this remains an interesting study as it reported a speci®c regional GABA level abnormality that was paralleled by increase in GABA receptor a subunit GABA concentrations " mRNA and decrease in GAT-1 mRNA (see below). The search for a GABAergic defect in schizophrenia also While most studies report low GABA levels in at least stimulated examination of GABA concentrations, both in some brain regions in schizophrenia, there is no clear brain tissue (see Table 1b) and in cerebrospinal ¯uid (CSF). consensus on the affected brain regions except for a GABA concentrations in brain tissue are unaffected by consistent ®nding of lower GABA in the amygdala (3 out agonal status (Spokes et al., 1979) but rise rapidly 1±2 h of 3 studies). Measurement of total GABA levels may be after death. The rise in GABA levels may continue even insufficiently sensitive to consistently detect a GABAergic 24 h post-mortem (Perry et al., 1981). Free CSF GABA defect affecting only a subpopulation of GABAergic cells. levels are unaffected by agonal status but decline The ®ndings of lower GABA in the amygdala in signi®cantly with age (Perry et al., 1979 ; Spokes et al., schizophrenia is interesting in light of recently reported 1979). Most studies controlled for age and post-mortem rat model in which a experimentally induced GABAergic processing, however drug history was not consistently dysfunction in the amygdala induces changes in the controlled for and the study of Perry et al. (1979) included GABAergic system of the hippocampus. The subregional a number of controls with various neurological illnesses. distribution of these changes is similar to ®ndings in Using a single-cation exchange column method lower previous post-mortem studies of schizophrenia (Benes, GABA concentrations was found in the nucleus accum- 1999 ; Berretta et al., 2001). bens and thalamus from schizophrenics compared with control (Perry et al., 1979). Another study used the same CSF studies method and did not ®nd lower GABA concentrations in the nucleus accumbens, medial dorsal thalamus, frontal Nine published studies examined GABA concentrations cortex or caudate of the schizophrenic subjects compared in CSF. The majority reported no difference between with controls (Perry et al., 1989). The authors suggested controls and schizophrenic patients (see Table 2). One that the ®rst study was ¯awed by lack of anatomical study found lower baseline CSF levels in a group of accuracy with respect to dissection of the nucleus schizophrenics compared with controls ; however it is not accumbens and the thalamus. Korpi et al. (1987) found no clear if a number of schizoaffective patients (previously effect of diagnosis on GABA levels in the nucleus mentioned in the report) were included in this group accumbens, frontal cortex, and caudate, but GABA was (Sternberg, 1980). If so, perhaps depression explained the 37±5 % lower in the amygdala in the schizophrenic group lower CSF GABA levels. All patients were drug free for compared with controls. Kutay et al. (1989) found lower 2 wk prior to the baseline lumbar puncture and GABA GABA levels in multiple brain regions including the levels showed no relationship with age, sex, or degree of amygdala, the hippocampus, frontal pole, superior tem- psychosis. This study also reported that a trial of pimozide poral cortex and thalamus. Toru et al. (1988) (see GAD increased GABA levels in the patients. Van Kammen et al. 164 B. P. Blum and J. J. Mann Table 1b. Presynaptic markers Marker Area Finding Comment Author GABA concentration Frontal cortex 5 Korpi et al. (1987) N. accumbens 5 Amygdala i 37±5%* GABA concentration Frontal pole i 40 % n ¯ 7 SCZ, Kutay et al. (1989) Hippocampus i 45 % 4 controls Sup. temp. cortex i 48 % Inf. temp. cortex 5 Amygdala i 61 % Dorsal thalamus i 72 % GABA concentration Frontal cortex 5 Perry et al. (1989) N. accumbens 5 Mediodorsal thalamus 5 GABA concentration Thalamus 5 Cross et al. (1979) N. accumbens 5 GABA concentration Thalamus i 21 %* Perry et al. (1979) N. accumbens i 35 %* GABA concentration Hippocampus 5 Spokes et al. (1980) Amygdala i 31±9%* N. accumbens i 13 % i 25 %* early Ventrolateral thalamus 5 onset cases only GABA concentration Dentate gyrus 5 n ¯ 7 Toru et al. (1988) CA 1±3 5 Subiculum 5 Post. hippocampus i 25 %* Sup., inf., and med. 5 temporal gyri Medial frontal and 5 orbitofrontal cortex GABA concentration BA 9 i 44 %* PMI controls " Ohnuma et al. (1999) BA 10 i 25 %* PMI SCZ BA 11 5 GABA-transaminase Amygdala 5 Sherif et al. (1992) Hippocampus 5 Serum GABA- 5 White et al. (1980) transaminase Serum GABA- 5 Reveley et al. (1980) transaminase GABA release BA 34 i 77±3%* n ¯ 5 Sherman et al. (1991) GABA release BA 8 i 68±9 %* Homogenate Sherman et al. (1991) (veratridine induced) GABA uptake sites BA 11 5 Simpson et al. (1989) ([ H]nipecotic acid) BA 38 i 18±9 %* left side Hippocampus i bilat.** Amygdala i bilat.** GABA uptake sites Hippocampus i 24 % left side Reynolds et al. (1990) ([$H]nipecotic acid) i 29 %* left side Sudden death cases i 21 % right side Amygdala 5 GABA uptake sites BA 11 5 Simpson et al. (1992a) ([$H]nipecotic acid) BA 38 i left side 15 % Males j right side 15±7% The GABAergic system in schizophrenia 165 Table 1b (cont.) Marker Area Finding Comment Author GABA uptake sites Putamen i bilat. E 50 %* Simpson et al. (1992b) ([ H]nipecotic acid) caudate N. accumbens 5 Globus pallidus 5 GABA uptake sites Ant. cingulate ; 5 Simpson et al. (1998a) ([ H]nipecotic acid) Ant. precentral 5 gyrus GABA uptake sites Putamen (head) 5 ([ H]nipecotic acid) Putamen (tail) j* Manchester collection Simpson et al. (1998b) Caudate j* Manchester and Gothenburg collection Globus pallidus 5 GAT-1 mRNA BA 9 i 18±1 %* Tissue sections Ohnuma et al. (1999) BA 10 5 BA 11 5 Table 2. CSF and serum GABA ®ndings in schizophrenia Measure Finding Comment Author GABA, CSF 5 n ¯ 17 schizophrenics, Lichtshtein et al. (1978) concentration 9 control GABA, CSF 5 n ¯ 7 schizophrenic, Gold et al. (1980) concentration 5 schizoaffective, 2 other psychosis, compared with neurological control group GABA, CSF i* n ¯ 17 schizoaffective Sternberg (1980) concentration and schizophrenic GABA, CSF 5 n ¯ 11 schizophrenic, Gerner and Hare (1981) concentration 29 controls GABA, CSF 5 between untreated and n ¯ 17 controls, Zimmer et al. (1981) concentration controls 9 untreated}7 treated j GABA in CSF schizophrenics with long-term neuroleptic tx. GABA, CSF j 45±7 %* In chronic schizophrenic McCarthy et al. (1981) concentration subset only GABA, CSF 5 all schizophrenic n ¯ 25 drug-free schizophrenic and van Kammen et al. (1982) concentration i 26 %* female pts only 5 schizoaffective GABA, CSF 5 n ¯ 20 chronic schizophenics Gerner et al. (1984) concentration GABA, CSF 5 n ¯ 19 schizophrenic Perry et al. (1989) concentration GABA, CSF and i plasma but not n ¯ 62 chronic van Kammen et al. (1998) plasma levels CSF GABA associated schizophenics with prefrontal but not global sulcal widening Plasma GABA 5 n ¯ 15 schizophrenics Petty and Sherman (1984) Platelet GABA- 5 n ¯ 22 schizophrenics Reveley et al. (1980) transaminase level Platelet GABA 5 n ¯ 14 schizophrenics White et al. (1980) transaminase level 166 B. P. Blum and J. J. Mann (1982) noted a signi®cant decrease in the female schizo- failed to ®nd any signi®cant difference in platelet GABA- phrenic sub-population compared to female controls while transaminase levels between schizophrenics and controls also reporting a tendency towards increased GABA levels (Reveley et al., 1980 ; White et al., 1980). No signi®cant with increased length of illness. That elevation of CSF effect of sex, psychotic state, length of illness or GABA levels may be correlated with length of schizo- medication treatment was noted in the study by White et phrenic illness ®nds support in a study by McCarthy et al. al. (1980) ; Reveley et al. (1980) reported no correlation (1981) in which a sub-population of chronic schizo- between age or sex and GABA-transaminase levels. Sherif phrenics had higher GABA levels compared to controls. et al. (1992) measured GABA-transaminase in brain However, Gerner et al. (1984) did not corroborate this homogenates from various regions including hippocam- suggestion. An increase in CSF GABA levels has been pus, amygdala, cingulate and frontal gyrus and found no found after 30 d treatment with sulpride and to be signi®cant difference between controls and undifferentiat- correlated with long-term neuroleptic treatment (Zimmer ed schizophrenics. Thus, there is no evidence of altered et al., 1981). However, Lichtshtein et al. (1978) noted a catabolism of GABA in schizophrenia. small but signi®cant decrease in CSF GABA levels after 2 months of neuroleptic treatment while Gattaz et al. (1986) GABA release and uptake observed no change in free CSF GABA levels in schizophrenic patients after 3 months of haloperidol Synaptosomal preparations are used in the study of treatment. Lastly, Zander et al. (1981) reported that synaptic function and neurotransmission in animal models. stopping chronic anti-psychotic medication treatment Synaptosomal preparations obtained up to 24 h post- produced no change in CSF GABA levels. CSF GABA is mortem from human brains are metabolically active and lowered in depressed patients and therefore comorbidity can release various neurotransmitters after veratrine must be considered in interpretation of these studies stimulation (Hardy et al., 1982). Using this model, (Gerner and Hare, 1981 ; Gold et al., 1980). A later study Sherman et al. (1991) compared schizophrenics and by Van Kammen et al. (1998) found that plasma GABA controls, with PMI of 20³7 h (mean³s.d.) and 23³7h, levels showed a signi®cant negative correlation with both respectively, and reported a signi®cantly lower veratri- prefrontal sulcal widening and ventricle}brain ratio on CT dine-induced release of glutamate and GABA but not scans but not to global sulcal widening in patients with aspartate in synaptosomes from temporal and frontal schizophrenia. CSF GABA levels did not correlate with cortex of the schizophrenic group. these CT measures but did show a negative correlation The concentration and duration of a neurotransmitter with age and age of onset. The disassociation between in the synaptic cleft is mostly regulated by rate of uptake CSF and serum GABA level is puzzling. One would by transporter proteins. Four GABA transporters have so expect CSF GABA to re¯ect brain pathology better than far been described (GAT-1, GAT-2, GAT-3 and BGT-1), plasma. Moreover, the plasma GABA ®nding may not be each varying in its localization pattern and pharma- correct since plasma GABA levels were not found to be cological pro®le (Borden, 1996). Simpson et al. (1989) lower in patients with schizophrenia (Petty and Sherman, reported signi®cantly lower binding of [$H]nipecotic acid 1984). to GABA-uptake sites in the left BA 38 (polar temporal), CSF GABA is not clearly lower in schizophrenia. There bilaterally in the amygdala and hippocampus in schizo- are insufficient studies in which the possible confounds of phrenic subjects compared to controls (see Table 1). This anti-psychotic medication treatment, comorbidity (in study did have sufficient numbers of age-matched subjects particular affective disorders), length of illness and sex are and controls with similar PMI ; agonal state effects were all controlled. Additionally, while pharmacological studies said to have been minimized by selection of subjects who in animals suggest that total CSF GABA concentrations had died acutely and were matched for cause of death. are mostly related to brain GABA (Bohlen et al., 1979 ; Possible medication in¯uence could not be entirely ruled Ferkany et al., 1979), it remains unknown to what degree out, although the authors reported that binding data from this is true in humans. A defect limited to a speci®c subjects that were drug-free were indistinguishable from subtype of GABAergic neurons, such as the chandelier those treated with neuroleptics. subtype (see below), may not be re¯ected in CSF GABA Comparing schizophrenic subjects to age- and PMI- levels. matched controls, Reynolds et al. (1990) found lower [$H]nipecotic acid binding in both groups in the left hippocampus compared to the right side but not so in the GABA-transaminase amygdala. The schizophrenic group tended towards lower Two studies measuring GABA-transaminase, the principal binding values in the left hippocampus compared with catabolic enzyme for GABA in the mammalian brain, controls (p ¯ 0±08) ; this tendency became statistically The GABAergic system in schizophrenia 167 signi®cant when subgroups of sudden-death cases were distribution and appear to be sufficiently sensitive to compared. The rationale for this distinction was that detect impaired input. There are approx. 100 times more nipecotic acid binding may be reduced in patients with GABA terminals on the apical dendrites than on the chronic respiratory illnesses (Czudek and Reynolds, 1990). proximal axon segment. Lewis et al. (2000) reported a Simpson et al. (1992a) used [$H]nipecotic acid to de®cit of the chandelier GABAergic neurons, which measure GABA-uptake sites in a series of schizophrenic speci®cally target the proximal axon segment. Such a and control brains in which cerebral atrophy had been localized GABAergic input defect may not be equally previously established and reported higher [$H]nipecotic detectable by assays of GAT, GAD, brain GABA or CSF acid binding in both groups in the right compared with GABA. left BA 38, lower left BA 38 binding and increased putaminal binding in the schizophrenic brains compared GABA receptors with controls. Subcortical GABA-uptake sites were further studied by Simpson et al. (1992b) in brains of 19 Two types of GABA receptors have been identi®ed in the schizophrenic subjects who had died with the diagnosis of human brain : the GABA receptor, which is associated schizophrenia along with 22 neuropsychiatrically normal with a chloride channel and mediates fast inhibitory controls, matched for age, gender ratio and PMI. In synaptic transmission and the GABA receptor which is contradiction to the above study, an approx. 50 % lower associated with potassium and calcium channels and is a [$H]nipecotic acid binding was seen in the putamen G protein-linked metabotrobic receptor (Bowery, 2000 ; bilaterally in the schizophrenic group. The binding of this Olsen and Homanics, 2000). The GABA receptor is ligand did not differ between the two groups in the thought to be a heteropentameric glycoprotein composed caudate, globus pallidum or nucleus accumbens. This of subunits of six distinct subclasses : a, b, c, d, e and q, the study also reported no correlation between binding to largest being the a subclass which includes six known GABA-uptake sites and length of the neuroleptic-free members (a ). In the adult mammalian brain, the subunit " ' period in a subgroup of medication-free schizophrenics. combination of a b c is thought to be the most common " # # Simpson et al. (1998a) measured [$H]nipecotic acid (Olsen and Homanics, 2000). binding to GABA-uptake sites in 11 brain regions from a Bennett et al. (1979) used tritiated GABA as a ligand group of 12 neuroleptic-treated chronic schizophrenia (9 (see Table 3) and reported that post-mortem binding in males, 3 females) and a group of normal controls (14 frontal cortex homogenates of schizophrenics was not males, 5 females). No signi®cant overall difference was signi®cantly different from controls. The study did report noted between the two groups in any of the 11 temporal alterations in serotonergic receptor binding. Control and and frontal lobe areas. The authors suggested these schizophrenia groups were not well matched for age or ®ndings might be in¯uenced by low uptake measurements sex ratio. The authors reported no correlation between in three of the female controls and large variance in the PMI or time frozen and receptor-binding results ; however hippocampal data. agonal and possible drug effects could not be excluded. A recent study examined [$H]nipecotic acid binding in Hanada et al. (1987) measured GABA receptor binding the basal ganglia from three brain collections (Manchester, using the GABA agonist [$H]muscimol and observed Gothenburg and Runwell) (Simpson et al., 1998b). The signi®cantly higher binding (B ) in both caudate and BA max schizophrenic (n ¯ 12±18) and the control subjects (n ¯ 9 in the chronic schizophrenic group as a whole compared 19±22) did not differ with respect to age, PMI or storage with controls. This ®nding survived subdivision into time. [$H]Nipecotic acid binding was higher in the sudden death and PTI subgroups in both regions of the schizophrenic groups compared to controls in the heads sudden-death subgroup but not in the caudate of the PTI of the caudate and putamen of the Manchester collection. subgroup. Higher binding was also noted in the caudate of the Benes et al. (1992) examined GABA receptor binding female schizophrenic subjects of the Gothenburg col- in the anterior cingulate gyrus in order to test a hypothesis lection ; the caudate-binding values obtained from this that upregulation of these receptors would follow the loss collection were 2- to 3-fold greater than those seen in the of cortical interneurons reported to occur in this region Manchester collection. Caudate-binding values were not and the prefrontal cortex of chronically psychotic patients reported for the Runwell collection. (Benes et al., 1991). By using a bicuculline-sensitive Several studies indicate that GABA uptake may be [$H]muscimol binding assay and a nuclear-track, coverslip- moderately lower in both the hippocampus ([$H]nipecotic emulsion technique, they counted autoradiographic grains acid binding studies) and in BA 9 (GAT-1 mRNA studies, per neuron and per 200 lm# of neuropil. [$H]Muscimol see below) of schizophrenic subjects compared with binding on neuronal cell bodies is 84 % higher in layer II controls. GABA-uptake sites may re¯ect GABA terminal and 74 % higher in layer III in the schizophrenic group 168 B. P. Blum and J. J. Mann Table 3. Postsynaptic markers Marker Area Finding Comment Author GABA receptor Frontal cortex 5 Homogenate Bennett et al. (1979) binding ([ H]GABA) GABA receptor BA 9 j 32 %* Homogenate Hanada et al. (1987) binding ([ H]muscimol) GABA receptor Cingulate cortex j 84 %* L II Tissue sections Benes et al. (1992) binding (bicuculline- j 74 %* L III sensitive [ H]muscimol) j 43 %* L II GABA receptor BA10 j 70 %* L II Benes et al. (1996a) binding (bicuculline- j 44 %* L III sensitive [ H]muscimol) j 48 %* L V j 90 %* L II large neurons j 66 %* L VI j 135 %* L VI sm. non-pyram. GABA receptor Area dentate Benes et al. (1996b) binding ([ H]muscimol) Molecular j 20±40 % Granular j 40±60 %* CA4, subiculum j 60±80 %* presubiculum j 60±80 %* CA3 j 74±90 %* j non-pyramidal cells 3x " pyram. CA1 j 22±36 % GABA receptor BA 9 j 18±5 %* Dean et al. (1999) binding ([ H]muscimol) GABA receptor BA 46 5 Akbarian et al. (1995a) subunit mRNAs GABA receptor BA 46 i 28 % (both isoforms) Huntsman et al. (1998) subunit mRNAs i 51±7%* (c S) (c S and c L) i 16±9% (c L) n ¯ 5 # # # GABA receptor BA 9 j 49±1%* n ¯ 6 Ohnuma et al. (1999) subunit mRNA BA 10 j 32±5% (p ¯ 0±051) BA 11 j 36±7% (p ¯ 0±0) GABA receptor Dentate gyrus Not quantitated Mizukami et al. (2000) immunoreactivity CA1-4 n ¯ 5 BZD receptor sites Medial, inferior i (p ! 0±01) Homogenates Kiuchi et al. (1989) [ H]¯unitrazepam and superior temporal gyri CA1-3 i (p ! 0±05) Dentate gyrus 5 BA 9, 10, 46 j 25 % BA 45 and 47 j (p ¯ 0±05 %) BA 11 and 12 j (p ¯ 0±01 %) BZD receptor sites Hippocampus i 29±0%* Homogenates Squires et al. (1993) [ H]¯unitrazepam Frontal cortex 5 n ¯ 3 BZD receptor sites Hippocampus 5 Homogenates Reynolds and Stroud (1993) [ H]¯unitrazepam BZD receptor sites BA 10 5 Homogenates Pandey et al. (1997) [ H]RO15-1788 BZD receptor sites Area dentate 5 Tissue sections Benes et al. (1997) [ H]-¯unitrazepam Subiculum j 20±30 %* Presubiculum j 15±20 %* CA1 5 CA2 5 CA3 (s. oriens only) j 30 %* CA4 5 The GABAergic system in schizophrenia 169 compared to normal controls. In layer I neuropil [$H] [$H]muscimol to GABA receptors, as well as decreased muscimol was increased in the schizophrenic group. PMIs [$H]ketanserin binding to 5-HT receptors in BA 9 of were similar in the two groups ; however, group sex ratios schizophrenic subjects compared to controls. The groups and cause of death were not mentioned. The schizophrenic were well matched for donor age, PMI, tissue pH and time group was signi®cantly younger than the control group frozen ; analysis of covariance showed that these potential but the authors discounted the possibility of a confound- confounds as well as ®nal neuroleptic dose did not effect ing effect as both younger and older schizophrenics had the comparison of ligand binding between the groups. elevated numbers of receptor sites compared to controls. Potential effects of agonal states were not addressed. The authors believed that elevation of [$H]muscimol In animal experiments, reduced neuronal activity can binding was not secondary to neuroleptic treatment, as a lead to decreased gene expression for a number of neuroleptic-naive and a minimally exposed patient both GABA receptor subunits (Hendry et al., 1990, 1994 ; had elevated binding. Huntsman et al., 1994). Akbarian et al. (1995a) used in-situ Benes et al. (1996b) also used a bicuculline-sensitive hybridization histochemisty to quantitate mRNA of the [$H]muscimol-binding assay to examine GABA receptor GABA receptor subunits a , a , a , b , b and c in the A A " # & " # # levels in the prefrontal cortex (BA 10) of 7 schizophrenic prefrontal cortex. The schizophrenic and control groups subjects and 16 normal controls. No difference in average showed similar laminar gene expression patterns with size of neuronal cell bodies was observed between the highest a , b , and c expression in layers III and IV, " # # two groups ; however, more grains per cell were found on highest a and b expression in layer II, and higher a # " & the large (pyramidal) neurons of layers II±VI (greatest in expression in layers IV±VI with peak expression in layer layer II) and on the small (non-pyramidal) neurons of layer IV. No signi®cant difference in expression of any of the VI in the schizophrenic subjects compared with controls. subunit genes was noted between the two groups. The 12 Although the control group was signi®cantly older and schizophrenic and 12 control subjects were matched for had a signi®cantly shorter mean PMI compared to the age, sex and PMI. schizophrenic group, no correlation was found between Huntsman et al. (1998) used in-situ hybridization these potential confounds and GABA binding. Two histochemisty and semi-quantitative reverse transcrip- schizophrenic subjects without history of neuroleptic tion±PCR to measure the relative abundance of two exposure had binding values that were lower than the species of mRNA of the c subunit of the GABA neuroleptic-treated schizophrenics and similar to the receptor in the prefrontal cortex of ®ve matched pairs of average of the control group. These same two neuroleptic- schizophrenics and controls. The c subunit, which is free schizophrenic subjects had exhibited a higher layer II necessary for high-affinity BZD binding, exists in two GABA receptor-binding value in a previous study of the forms : short (c S) and long (c L), which differ by a # # anterior cingulate gyrus (Benes, 1992) compared with the functionally signi®cant 8-amino-acid insert. The laminar schizophrenic group as a whole indicating that the higher pattern of c subunit mRNA labelling was consistent with GABA receptor binding in the prefrontal cortex of the past reports for both schizophrenics and controls. Al- schizophrenic group may not be simply a medication though the schizophrenic group was found to have lower effect. c message labelling in each of the six cortical levels, this Benes et al. (1996a), using brain tissue from the same difference reached statistical signi®cance in only layers II subjects in the above study (with the addition of one and III. The authors reported a lower level (average subject to the schizophrenia group), reported higher 51±7%, p ! 0±001) of short (c S) mRNA (but only 16±9% [$H]muscimol in subregions of the hippocampus of the lower long (c L) mRNA) in the prefrontal cortex of the schizophrenic group compared with controls. Increases of schizophrenic group compared with their matched con- 90 % (stratum oriens of CA3), of 74 % (stratum pyrami- trols. The authors speculated that this relative overabun- dales of CA3), of 60±73 % (subiculum and presubiculum) dance of the long (c L) mRNA in the prefrontal cortex of and of 22±36 % were seen in the CA1 subregion (ranges schizophrenics would result in GABA receptors of indicating layer differences within a subregion). Increased decreased functionality. Agonal effects were not discussed GABA binding in the subregion CA3 was limited to but the authors expressed concern about possible medi- non-pyramidal cells while binding increases in the CA1 cation effects. subregion were noted only on pyramidal cells. The author Ohnuma et al. (1999) measured a subunit mRNA postulated that these subregional increases in GABA expression in BA 9, 10, and 11 of 6 schizophrenics and 12 receptor binding might re¯ect increased vulnerability of controls and found a general increase in the schizophrenic certain subpopulation of GABAergic neurons to injury group which attained statistical signi®cance in the large during development. cells of layer V of BA 9 and in layer III of BA 10. The Dean et al. (1999) reported increased binding of patient group was comprised of neuroleptic-treated 170 B. P. Blum and J. J. Mann chronic schizophrenics who had a shorter averaged PMI controls with matching sex compositions and ages. than controls. Medication history was not reported. One study examined the anatomical distribution of Squires et al. (1993) found lower [$H]¯unitrazepam immunolabelled GABA receptors in the hippocampus of binding in a schizophrenic group compared with controls, 5 chronic schizophrenics and 3 controls matched for age with differences reaching statistical signi®cance in the and PMI (Mizukami et al., 2000). Schizophrenic subjects somatomotor and cingulate cortex but not in other were reported to be resistant to neuroleptic treatment ; cortical regions such as the frontal cortex. Lower binding however cause of death and treatment status at time of in the schizophrenic group was also noted in the globus death were not reported. The authors found less immuno- pallidus, hippocampus and cerebellar cortex (vermis) but labelling of the mossy cells in CA4 and the pyramidal cells not in the putamen. The authors speculated that these in CA1±3 in the schizophrenic subjects compared to the reductions in binding might represent the loss of gluta- controls. The granule cells of the dentate gyrus appeared matergic (pyramidal) cells. Four of 15 schizophrenic unstained in the schizophrenic subjects whereas staining subjects were suicide victims whereas the nine controls in controls was reported as moderate. In all regions the were victims of traffic accidents. Past studies of BZD degree of staining of interneurons was similar in both receptors in suicide victims found altered (Cheetham et al., subject types. 1988) and unaltered binding (Manchon et al., 1987 ; In summary, GABA receptor binding is higher in Rochet et al., 1992 ; Stocks et al., 1990) ; therefore the use schizophrenia in cortical regions generally regarded as of suicide victims may be a confound. The schizophrenic important in the pathophysiology of schizophrenia. subjects were reported to be drug-free for months prior to Somewhat at odds with this observation is the tendency death ; the average PMI appears to have been signi®cantly towards less subunit mRNA in the prefrontal cortex of longer for the schizophrenic group (Squires et al., 1993). schizophrenic subjects in two studies. These receptor To further study the relationships between suicide, changes may represent upregulation in response to schizophrenia and BZD receptor binding, Pandey et al. reduced GABAergic input. What remains unclear is the (1997) examined binding of the selective, high-affinity functional signi®cance of alterations in binding or gene radioligand [$H]RO15-1788 in prefrontal cortex B max expression. The functional response mediated by these values (BA 10) homogenates from 13 suicide victims receptors may be impaired and counteract the bene®ts of without schizophrenia, 8 schizophrenic suicide victims, 5 up-regulation. Studies of receptor coupling and signal non-suicide schizophrenic subjects and 15 normal con- transduction are needed. trols. The B of BZD receptors in the prefrontal cortex max was higher in suicide victims, largely due to increased B in the suicide victims who had died by violent max means. Overall, the B of the schizophrenic subjects did max BZD binding studies not differ from controls ; however, the sample size was The therapeutic efficacy of BZDs as anxiolytic agents is small. attributed to their ability to potentiate GABA receptor- Benes et al. (1997) assayed BZD binding with [$H]¯uni- mediated inhibition by increasing the receptors affinity trazepam in hippocampal tissue sections from the same for GABA. Selectivity of BZD binding to the GABA schizophrenic and control subjects used in a previous receptor is determined by speci®c amino-acid residues study (Benes et al., 1996a). After normalization of the in the c and the a subunits (Mohler et al., 2000). data, the ratios of BZD binding to GABA binding in Kiuchi et al. (1989) assayed [$H]¯unitrazepam binding controls was similar throughout most of the hippocampal in homogenates from multiple cortical regions of brains region except in the inner and outer molecular layers of from schizophrenic and control subjects and reported the area dentata where higher BZD binding was observed. signi®cantly higher binding in the medial frontal cortex [$H]Flunitrazepam binding was found to be only modestly orbitofrontal cortex, orbital cortex, medial and inferior higher in the stratum oriens of the CA3, the subiculum temporal gyri, cornu Ammonis 1±3 of the hippocampus and the presubiculum of the schizophrenic subjects com- and putamen of the schizophrenic subjects compared with pared with controls. As the magnitude of these increases controls (see Table 3). No signi®cant differences in binding did not match the increases in GABA binding in these were found in other areas. Medication effects might be a regions, the authors speculated that the regulation of the confound in this study and agonal state issues were BZD-binding elements might be uncoupled from the regu- unaddressed. lation of the GABA receptor. The authors noted that Reynolds and Stroud (1993) found no difference in such an uncoupling phenomena was reported in the cere- [$H]¯unitrazepam binding in hippocampal homogenates bellum of the stagger mouse (Luntz-Leybman et al., 1995). between a group of 15 schizophrenic subjects and normal Taken as a group, these papers on BZD binding in schizo- The GABAergic system in schizophrenia 171 phrenia do not provide a consensus about BZD binding pyramidal cell output ; they also appear to receive direct in examined regions of the frontal or temporal lobes. synaptic input from mesocortical dopamine and thalamo- cortical glutamatergic projection (Muly III et al., 1998 ; Sesack et al., 1995, 1998). Calcium-binding proteins as markers of GABAergic An early study of calcium-binding proteins in schizo- neurons phrenia used CR and calbindin (CB) immunohistochemical In the prefrontal cortex of primates, sub-populations of labelling of tissue from prefrontal cortical areas 9 and 46 GABAergic interneurons can be classi®ed based on obtained from 1 schizoaffective and 4 schizophrenic morphological characteristics, synaptic targets or the subjects and 5 controls matched for age, sex and PMI (see presence of different calcium-binding proteins (Conde! et Table 4) (Daviss and Lewis, 1995). One of the schizo- al., 1994 ; Lund and Lewis, 1993). The calcium-binding phrenic subjects died by suicide ; the cause of death listed protein parvalbumin is found primarily in the wide-basket for the remainder of subjects are consistent with short and chandelier subclasses of GABA neurons. The axon agonal periods. The authors found a 50±70 % greater terminals of the chandelier neurons synapse on the initial density of the CB-immunoreactive (CB-IR) and a 10±20 % axon segments of pyramidal cell. The axon terminals of (non-signi®cant) greater density of the CR-immunoreac- the wide- basket neurons synapse on the cell bodies and tive (CR-IR) non-pyramidal neurons of both cortical areas dendrites of pyramidal cells. GABA neurons in the double- in the schizophrenic group compared with the controls. bouquet subclass contain calretinin (CR) and have terminal The authors noted small sample size, lack of stereological axons that synapse onto the dendritic shafts of both methodology and potential medication effects as caveats. pyramidal and non-pyramidal neurons. The parvalbumin- Beasley and Reynolds (1997) used a monoclonal containing GABA neurons of the chandelier subclass have antibody against parvalbumin to quantitate parvalbumin- attracted the most scrutiny in studies of schizophrenia containing chandelier and wide-basket GABA neurons in because their synaptic targeting of the axon initial tissue sections from BA 10 obtained from schizophrenic segment of pyramidal cells suggest a strong in¯uence on and control subjects. The authors reported fewer parval- Table 4. Calcium protein markers of non-pyramidal neurons in schizophrenia Marker Area Finding Comment Author Non-pyramidal neurons BA 9 and 46 Daviss and Lewis (1995) Calbindin-IR j 50±70 %* Calretinin-IR j 10±20 % Parvalbumin-IR neurons BA 10 i* layer III Beasley and Reynolds (1997) i* layer IV Parvalbumin-IR neurons BA 9 5 Woo et al. (1997) BA 46 5 BA 17 5 Parvalbumin-IR neurons Ant. cingulate j layers Va±Vb Kalus et al. (1997) cortex GAT-1-IR cartridges BA 9 i 40 %* Woo et al. (1998) (chandelier cells) BA 46 i 40 %* GAT-1-IR cartridges BA 46 i 27±7 %* layer II±IIIb Pierri et al. (1999) (chandelier cells) i 31±5 %* layer IIIb±IV 5 layer VI Parvalbumin-IR neurons BA 9 and 5 Results previously Lewis (2000) BA 46 reported in Woo et al. (1997) GAT-1-IR cartridges BA 9 and i 40 %* Results previously Lewis (2000) (chandelier cells) BA 46 reported inWoo et al. (1998) Parvalbumin-IR neurons BA 9 and i* Reynolds and Beasley (2001) BA 46 Calbindin-IR neurons i* Calretinin-IR neurons 5 172 B. P. Blum and J. J. Mann bumin-positive cells in the schizophrenic subjects com- 30 schizophrenics [15 of the comparison triads had been pared with the normal controls. Differences reached used in a previous study (Woo et al., 1998)] had statistical signi®cance only in layers III and IV. No group signi®cantly lower GAT-1-IR cartridge density in layers difference was found in cortical thickness. Age, sex, and II±IIIa and IIIb±IV. The schizophrenic subjects were duration of illness did not have an effect on cell counts. matched to controls by sex, age and PMI. Signi®cant The authors did not use a stereological method. The numbers of subjects in both the schizophrenia group and question of an effect of neuroleptics on parvalbumin psychiatric control group but not the normal control expression and cell counts was left open. group had histories of substance abuse or were suicide Woo et al. (1997) examined parvalbumin-IR local victims. Medication effects were not apparent on GAT-1- circuit GABAergic neurons in tissue sections from BA 9, IR cartridge density in prefrontal cortex of male Cynomol- 46 (prefrontal) and 17 (visual) obtained from 15 schizo- gus monkeys were treated for 9±12 months with phrenic subjects and sex-matched controls and detected haloperidol decanoate and benztropine mesylate. no signi®cant difference in their densities between the GAT-1 mRNA levels were quantitated in 10 pairs of schizophrenics and controls. As the authors found no schizophrenic subjects and controls (see Volk et al., 2000) somal size differences between the two subject groups, in a study which sought to determine if lower GAT-1 the inability to perform absolute cell counts was not density in the prefrontal cortex was accompanied by thought to be a confound. However, differences in lower GAT-1 gene expression (Volk et al., 2001). A neuropil or tissue shrinkage could be critical for density threshold of 2-fold background was used to exclude non- measures. Cause of death and medication histories of the speci®c labelling and a somal size criterion of greater than subjects were not reported. 50 lm# was used to exclude glial cells. GAT-1 mRNA- More parvalbumin-IR GABA interneurons in layers Va positive neuron density was lower (21±33 %) in layer I, and Vb of the anterior cingulate cortex was found in layer II, the super®cial portion of layer III, and at the schizophrenics compared with controls, but the density of boundary of layers III±IV in the schizophrenic group Nissl-stained neuron pro®les did not differ in any of the compared with controls. Grain density per neuron was layers (Kalus et al., 1997). Stereological methods were not also signi®cantly decreased (11 %, p ¯ 0±009) in the employed. The two groups differed signi®cantly in schizophrenic group only at the layers III±IV border and average PMI ; disparities in tissue shrinkage, medication cross-sectional size did not differ signi®cantly between histories and agonal states may have confounded the the two groups. This study also compared GAT-1 mRNA results. labelling between 4 haloperidol- and benztropine mesy- Woo et al. (1998) used an antibody against the GABA late-treated Cynomolgus monkeys and 4 untreated con- transporter GAT-1 to identify the distinctive vertical trols and reported that after 9±12 months of treatment arrays of chandelier axons known as cartridges. This there were no signi®cant differences. The authors con- study included 15 schizophrenic subjects matched by age, cluded that GAT-1 expression in the prefrontal cortex of sex and PMI to both a normal control and a non- schizophrenics is unaltered overall, but that it may be schizophrenic psychiatric group. The relative density of lower in the chandelier class of GABAergic cells. The GAT-1-IR cartridges, assessed by stereological methods, authors noted that lower density of GAT-1 mRNA- was lower in the schizophrenic subjects across layers II-VI positive neurons is congruent with a previous ®nding of in both BA 9 and 46 compared with both the psychiatric laminar-speci®c decreases in GAD -positive neuronal '( and normal controls. Density of CR-IR axon boutons in but not synaptophysin-mRNA-positive neuronal densi- layers II±IIIa did not differ between the schizophrenic and ties (Volk et al., 2000). normal control subjects. The schizophrenic group included Overall, it appears that there may be fewer GAT-1-IR two suicide victims, the psychiatric group included 12 axon cartridges consistent with less GABAergic inhibition suicide victims and normal control group had no suicide at the proximal axon segment of pyramidal cells by cases ; cause of death in the remaining subjects was not parvalbumin-positive chandelier cells. Of the calcium- reported. The majority of the schizophrenic group had binding proteins, parvalbumin alone is expressed later in been treated with neuroleptic medication ; however, the foetal development in GABAergic interneurons. Late authors noted that two of the schizophrenic subjects who expression of parvalbumin is hypothesized to lead to a had been off medications for a signi®cant time before ` window of vulnerability ' in which an insult to the foetus death also had GAT-1 cartridge densities that were lower leads to glutamate receptor stimulation and cytotoxic than control densities. calcium in¯ux (Reynolds and Beasley, 2001). An important Pierri et al. (1999) also examined the laminar densities question to be resolved is whether or not the abnormality of GAT-1-IR cartridges and found that in comparison in the parvalbumin-class interneurons involves a loss of with a psychiatric and a normal control group, a group of such cells (Beasley and Reynolds, 1997 ; Reynolds and The GABAergic system in schizophrenia 173 Beasley, 2001) or is limited to a decrease in the number of that a GABAergic defect may be speci®c for the chandelier axon cartridges (Pierri et al., 1999). Of the calcium-protein class interneurons (Beasley and Reynolds, 1997 ; Lewis, positive GABAergic interneurons in the adult mouse 2000 ; Reynolds et al., 2000). Fewer chandelier-class cortex, parvalbumin-class interneurons alone do not GABAergic synapsing onto cortical pyramidal cells may express reelin protein, suggesting that the abnormality in contribute to impaired ability to perform dopamine- this class of interneurons is not related to the de®cits in dependent functions such as working memory (Goldman- reelin reported in schizophrenia (Alca! ntara et al., 1998 ; Rakic, 1996 ; Lewis et al., 1999). Decreases in dopamine Guidotti et al., 2000 ; Impagnatiello et al., 1998). input into the prefrontal cortex may also lead to decreased cortical glutamatergic input to the ventral striatum} ventral pallidum. This may lead to a decrease in tonic Non-pyramidal cell counts dopamine release resulting in a decreased ability to A non-stereological study of 9 chronic schizophrenic, 9 regulate phasic dopamine release in mesolimbic circuits schizoaffective and 12 control subjects reported fewer leading to positive symptoms (Grace, 1991 ; Moore et al., small neurons in layers I and II of the prefrontal cortex 1999). Alternatively, a decrease in cortical glutamatergic (BA 10) and in layers II±VI of the anterior cingulate (BA activity onto striatal GABAergic projection neurons may 24) in the two patient groups compared with controls lead to a decrease in the inhibitory effects of the indirect (Benes et al., 1991) These decreases tended to be greater striatothalmic pathway on the thalamus. Such an effect in the schizoaffective subgroup. Glial cell numbers did not may decrease the ability of the thalamus to ®lter off differ between the groups nor did pyramidal cell numbers excessive or irrelevant stimuli (Carlsson et al., 2001). except in layer V of the patient group in which had Some evidence is also presented for the existence of signi®cantly higher counts were observed. GABAergic defect in regions of the temporal lobe, in A recent stereological study of post-mortem tissue particular in the hippocampus. In this region, there also from the hippocampus obtained from 10 schizophrenic appears to be de®cits in GABA uptake (Reynolds et al., and 10 age- and PMI-matched controls found fewer 1990 ; Simpson et al., 1989) with increased (and possibly numbers of non-pyramidal cells in CA2 sector of the compensatory) GABA receptor binding (Benes et al., schizophrenics compared with controls (Benes et al., 1996a). Studies of BZD receptor binding have generated 1998). A similar ®nding was reported in a group of four con¯icting results in both frontal cortical regions and in bipolar patient also included in this study. Numbers of the hippocampus. The only study employing the use of pyramidal cells did not differ between the groups. Three tissue sections reported modest regional increases in of the schizophrenic subjects were suicide victims and hippocampal BZD binding in the schizophrenic group both groups may have been partly composed of subjects that suggest an uncoupling of the BZD and GABA with prolonged agonal intervals. Two schizophrenic receptors (Benes et al., 1997). Whether or not this re¯ects subjects who were neuroleptic-free for at least 1 yr also a true uncoupling of the BZD and GABA receptors and had decreased non-pyramidal counts in the sector CA2. is related to an abnormality in c-subunit processing There may be fewer non-pyramidal neurons in the (Huntsman et al., 1998) remains to be determined. prefrontal cortex in schizophrenia, further evidence of a The full anatomical distribution of post-mortem ®nd- GABAergic de®cit. ings in the GABAergic system in schizophrenia is not known with certainty because most studies have selec- tively examined certain regions. Systematic mapping Conclusion studies of the human neocortex are lacking for most Substantial evidence argues for a defect in the GABAergic GABAergic markers. The authors also wish to emphasize system of the frontal cortex in schizophrenia, particularly that many of the ®ndings reviewed in this article remain in the prefrontal region and to a lesser degree in the unreplicated. Interpretation of abnormal ®ndings in the anterior cingulate gyrus. A coherent pattern can be GABAergic system in schizophrenia should be tempered described : lower GAD mRNA and protein (Akbarian et by lack of information on functional changes in '( al., 1995b ; Guidotti et al., 2000 ; Impagnatiello et al., GABAergic transmission, the awareness that schizophre- 1998 ; Volk et al., 2000) is possibly paralleled by lower nia may be a heterogeneous set of disorders and that GABA concentrations (Kutay et al., 1989), less release of multiple defects may cause the same basic illness. One GABA (Sherman et al., 1991), lower GAT-1 mRNA also needs to keep in mind the likely complexity of the (Ohnuma et al., 1999 ; Volk et al., 2001) and up-regulation GABAergic system ; a system in which the major synthetic of GABA sites (Benes et al., 1992, 1996b ; Dean et al., enzyme occurs in two distinct forms at the genomic level, 1999 ; Hanada et al., 1987). the number of recognized receptor subtypes is approx. 20 Use of calcium-binding proteins as markers indicates (Olsen and Homanics, 2000). Complexity is also added by 174 B. P. Blum and J. J. Mann the fact that GABAergic neurons interact with multiple Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL (1991). De®cits in small interneurons in prefrontal and neurotransmitters systems, exist in at least 14 distinct cingulate cortices of schizophrenic and schizoaffective electrophysiological subtypes (Gupta et al., 2000) and are patients. Archives of General Psychiatry 48, 996±1001. involved in virtually every brain circuit. Additionally, one Benes FM, Todtenkopf MS, Logiotatos P, Williams M (2000). needs to use caution in interpreting ®ndings from any Glutamate decarboxylase -immunoreactive terminals in study that has not controlled for medication history. For '& cingulate and prefrontal cortices of schizophrenic and example, chronic haloperidol treatment increases the size bipolar brain. Journal of Chemical Neuroanatomy 20, of GABA-IR axosomatic terminals in the medial prefrontal 259±269. cortex of rats (Vincent et al., 1994) and increases GABA Benes FM, Vincent SL, Alsterberg G, Bird ED, SanGiovanni JP receptor binding in the substantia nigra, the latter effect (1992). Increased GABA receptor binding in super®cial being partially reversed after 8 d of treatment cessation layers of cingulate cortex in schizophrenics. Journal of (Huffman and Ticku, 1983). Part of the antipsychotic Neuroscience 12, 924±929. effects of medications such as haloperidol may be due to Benes FM, Vincent SL, Marie A, Khan Y (1996b). Up- such secondary changes in the GABAergic system. regulation of GABA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 75, 1021±1031. Benes FM, Wickramasinghe R, Vincent SL, Khan Y, References Todtenkopf M (1997). Uncoupling of GABA and Adler LE, Olincy A, Waldo M, Harris JG, Griffith J, Stevens benzodiazepine receptor binding activity in the K, Flach K, Nagamoto H, Bickford P, Leonard S, Freedman hippocampal formation of schizophrenic brain. Brain R (1998). Schizophrenia, sensory gating, and nicotinic Research 755, 121±129. receptors. Schizophrenia Bulletin 24, 189±202. Bennett Jr. JP, Enna SJ, Bylund DB, Gillin JC, Wyatt RJ, Akbarian S, Huntsman MM, Kim JJ, Tafazzoli A, Potkin SG, Snyder SH (1979). Neurotransmitter receptors in frontal Bunney Jr. WE, Jones EG (1995a). GABA receptor subunit cortex of schizophrenics. Archives of General Psychiatry 36, gene expression in human prefrontal cortex : comparison of 927±934. schizophrenics and controls. Cerebral Cortex 5, 550±560. Berretta S, Munno DW, Benes FM (2001). Amygdalar Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, activation alters the hippocampal GABA system, ` partial ' Bunney Jr. WE, Jones EG (1995b). Gene expression for modelling for postmortem changes in schizophrenia. Journal glutamic acid decarboxylase is reduced without loss of of Comparative Neurology 431, 129±138. neurons in prefrontal cortex of schizophrenics. Archives of Bird ED, Spokes EG, Barnes J, MacKay AV, Iversen LL, General Psychiatry 52, 258±266. Shepherd M (1977). Increased brain dopamine and reduced Alcantara S, Ruiz M, D'Arcangelo G, Ezan F, de Lecea L, glutamic acid decarboxylase and choline acetyl transferase Curran T, Sotelo C, Soriano E (1998). Regional and cellular activity in schizophrenia and related psychoses. Lancet 2, patterns of reelin mRNA expression in the forebrain of the 1157±1158. developing and adult mouse. Journal of Neuroscience 18, Bloom FE, Iversen LL (1971). Localizing $H-GABA in nerve 7779±7799. terminals of rat cerebral cortex by electron microscopic Awapara J, Landua AJ, Fuerst R, Seale B (1950). Free c- autoradiography. Nature 229, 628±630. aminobutyric acid in the brain. Journal of Biological Bo$ hlen P, Huot S, Palfreyman MG (1979). The relationship Chemistry 187, 35±39. between GABA concentrations in brain and cerebrospinal Bazemore AW, Elliott KAC, Florey E (1957). Isolation of ¯uid. Brain Research 167, 297±305. Factor I. Journal of Neurochemistry 1, 334±339. Borden LA (1996). GABA transporter heterogeneity, Beasley CL, Reynolds GP (1997). Parvalbumin- pharmacology and cellular localization. Neurochemistry immunoreactive neurons are reduced in the prefrontal International 29, 335±356. cortex of schizophrenics. Schizophrenia Research 24, Bowery N (2000). GABA Receptors : structure and function. 349±355. In : Martin D, Olsen R (Eds.), GABA in the Nervous System, Benes FM (1999). Evidence for altered trisynaptic circuitry in The View at Fifty Years (pp. 233±244). Philadelphia : schizophrenic hippocampus. Biological Psychiatry 46, Lippincott Williams & Wilkins. 589±599. Breier A, Su TP, Saunder R, Carson RE, Kolachana BS, De Benes FM, Khan Y, Vincent SL, Wickramasinghe R (1996a). Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra Differences in the subregional and cellular distribution of AK, Eckelman WC, Pickar D (1997). Schizophrenia is GABAA receptor binding in the hippocampal formation of associated with elevated amphetamine-induced synaptic schizophrenic brain. Synapse 22, 338±349. dopamine concentrations : evidence form a novel positron Benes FM, Kwok EW, Vincent SL, Todtenkopf MS (1998). A emission tomography method. Proceedings of the National reduction of nonpyramidal cells in sector CA2 of Academy of Sciences USA 94, 2569±2574. schizophrenics and manic depressives. Biological Psychiatry Bu DF, Erlander MG, Hitz BC, Tillakaratne NJ, Kaufman DL, 44, 88±97. Wagner-McPherson CB, Evans GA, Tobin AJ (1992). Two The GABAergic system in schizophrenia 175 human glutamate decarboxylases, 65-kDa GAD and 67- Dudel J, Gryder R, Kaji A, Kuffler SW, Potter DD (1963). kDa GAD, are each encoded by a single gene. Proceedings Gamma-aminobutyric acid and other blocking compounds of the National Academy of Sciences USA 89, 2115±2119. in crustacea I. Central nervous system. Journal of Carlsson A (1988). The current status of the dopamine Neurophysiology 26, 721±728. hypothesis of schizophrenia. Neuropsychopharmacology 1, Erlander MG, Tobin AJ (1991). The structural and functional 179±186. heterogeneity of glutamic acid decarboxylase, a review. Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Neurochemical Research 16, 215±226. Carlsson ML (2001). Interactions between monoamines, Esclapez M, Tillakaratne NJK, Kaufman DL, Tobin AJ, Houser glutamate, and GABA in schizophrenia, new evidence. CR (1994). Comparative localization of two forms of Annual Review of Pharmacology and Toxicology 41, 237±260. glutamic acid decarboxylase and their mRNAs in rat brain Cheetham SC, Crompton MR, Katona CLE, Parker SJ, Horton supports the concept of functional differences between the RW (1988). Brain GABA }benzodiazepine binding sites A forms. Journal of Neuroscience 14, 1834±1855. and glutamic acid decarboxylase activity in depressed Feldblum S, Erlander MG, Tobin AJ (1993). Different suicide victims. Brain Research 460, 114±123. distributions of GAD65 and GAD67 mRNAs suggest that Conde F, Lund JS, Jacobowitz DM, Baimbridge KG, Lewis the two glutamate decarboxylases play distinctive DA (1994). Local circuit neurons immunoreactive for functional roles. Journal of Neuroscience Research 34, calretinin, calbindin D-28k or parvalbumin in monkey 689±706. prefrontal cortex : distribution and morphology. Journal of Ferkany JW, Butler IJ, Enna SJ (1979). Effect of drugs on rat Comparative Neurology 341, 95±116. brain, cerebrospinal ¯uid and blood GABA content. Journal Cross AJ, Crow TJ, Owen F (1979). Gamma-aminobutyric of Neurochemistry 33, 29±33. acid in the brain in schizophrenia. Lancet 1, 560±561. Florey E (1991). GABA : history and perspectives. Canadian Cross AJ, Owen F (1979). The activities of glutamic acid Journal of Physiology and Pharmacology 69, 1049±1056. decarboxylase and choline acetyltransferase in post-mortem Florey E, McLennan H (1955). The release of an inhibitory brains of schizophrenics and controls. Biochemical Society substance from mammalian brain and its action on Transactions 7, 145±146. peripheral synaptic transmission. Journal of Physiology Crow TJ, Owen F, Cross AJ, Lofthouse R, Longden A (1978). (London) 129, 384±392. Brain biochemistry in schizophrenia. Lancet 1, 36±37. Fuxe K, Perez de la Mora M, Ho$ kfelt T (1977). GABA±DA Curran T, D'Arcangelo G (1998). Role of reelin in the control interactions and their possible relation to schizophrenia. In : of brain development. Brain Research Brain Research Reviews Shagass C, Gershon S, Friedhoff AJ (Eds.), Psychopathology 26, 285±294. $ and Brain Pathology (pp. 97±111). New York : Raven Press. Czudek C, Reynolds GP (1990). [ H]nipecotic acid binding to Garbutt JC, van Kammen DP (1983). The interaction between gamma-aminobutyric acid uptake sites in postmortem human brain. Journal of Neurochemistry 55, 165±168. GABA and dopamine : implications for schizophrenia. Daviss SR, Lewis DA (1995). Local circuit neurons of the Schizophrenia Bulletin 9, 336±353. prefrontal cortex in schizophrenia, selective increase in the Gattaz WF, Roberts E, Beckmann H (1986). Cerebrospinal density of calbindin-immunoreactive neurons. Psychiatry ¯uid concentrations of free GABA in schizophrenia, no Research 59, 81±96. changes after haloperidol treatment. Journal of Neural Deakin JFW, Simpson MDC (1997). A two-process theory of Transmission 66, 69±73. schizophrenia, evidence from studies in post-mortem brain. Gerner RH, Fairbanks L, Anderson GM, Young JG, Scheinin Journal of Psychiatric Research 31, 277±295. M, Linnoila M, Hare TA, Shaywitz BA, Cohen DJ (1984). Dean B (2001). A predicted cortical serotonergic} CSF neurochemistry in depressed, manic, and schizophrenic cholinergic}GABAergic interface as a site of pathology patients compared with that of normal controls. American in schizophrenia. Clinical and Experimental Pharmacology Journal of Psychiatry 141, 1533±1540. and Physiology 28, 74±78. Gerner RH, Hare TA (1981). CSF GABA in normal subjects Dean B, Hussain T, Hayes W, Scarr E, Kitsoulis S, Hill C, and patients with depression, schizophrenia, mania, and Opeskin K, Copolov DL (1999). Changes in serotonin A anorexia nervosa. American Journal of Psychiatry 138, and GABA receptors in schizophrenia, studies on the 1098±1101. human dorsolateral prefrontal cortex. Journal of Gold BI, Bowers Jr. MB, Roth RH, Sweeney DW (1980). Neurochemistry 72, 1593±1599. GABA levels in CSF of patients with psychiatric disorders. Deutsch SI, Rosse RB, Schwartz BL, Mastropaolo J (2001). A American Journal of Psychiatry 137, 362±364. revised excitotoxic hypothesis of schizophrenia, therapeutic Goldman-Rakic PS (1996). Regional and cellular fractionation implications. Clinical Neuropharmacology 24, 43±49. of working memory. Proceedings of the National Academy of Dewey SL, Smith GS, Logan J, Brodie JD, Yu DW, Ferrieri Sciences USA 93, 13473±13480. RA, King PT, MacGregor RR, Martin TP, Wolf AP (1992). Grace AA (1991). Phasic versus tonic dopamine release and GABAergic inhibition of endogenous dopamine release the modulation of dopamine system responsivity, a measured in vivo with 11C-raclopride and positron hypothesis for the etiology of schizophrenia. Neuroscience emission tomography. Journal of Neuroscience 12, 41, 1±24. 3773±3780. 176 B. P. Blum and J. J. Mann Guidotti A, Auta J, Davis JM, Gerevini VD, Dwivedi Y, Kaufman DL, Houser CR, Tobin AJ (1991). Two forms of the Grayson DR, Impagnatiello F, Pandey G, Pesold C, Sharma c-aminobutyric acid synthetic enzyme glutamate R, Uzunov D, Costa E (2000). Decrease in reelin and decarboxylase have distinct intraneuronal distributions and glutamic acid decarboxylase (GAD ) expression in cofactor interactions. Journal of Neurochemistry 56, 720±723. '( '( schizophrenia and bipolar disorder, a postmortem brain Keverne EB (1999). GABA-ergic neurons and the study. Archives of General Psychiatry 57, 1061±1069. neurobiology of schizophrenia and other psychoses. Brain Gupta A, Wang Y, Markram H (2000). Organizing principles Research Bulletin 48, 467±473. for a diversity of GABAergic interneurons and synapses in Kiuchi Y, Kobayashi T, Takeuchi J, Shimizu H, Ogata H, Toru the neocortex. Science 287, 273±278. M (1989). Benzodiazepine receptors increase in post- Hanada S, Mita T, Nishino N, Tanaka C (1987). [$H]muscimol mortem brain of chronic schizophrenics. European Archives binding sites increased in autopsied brains of chronic of Psychiatry and Neurological Sciences 239, 71±78. schizophrenics. Life Sciences 40, 259±266. Korpi ER, Kleinman JE, Goodman SI, Wyatt RJ (1987). Hardy JA, Dodd PR, Oakley AE, Kidd AM, Perry RH, Neurotransmitter amino acids in post-mortem brains of Edwardson JA (1982). Use of post-mortem human chronic schizophrenic patients. Psychiatry Research 22, synaptosomes for studies of metabolism and transmitter 291±301. amino acid release. Neuroscience Letters 33, 317±322. Kravitz EA, Kuffler SW, Potter DD (1963). Gamma- Hendry SHC, Fuchs J, deBlas AL, Jones EG (1990). aminobutyric acid and other blocking compounds in Distribution and plasticity of immunocytochemically crustaceans. III. Their relative concentrations in separated localized GABA receptors in adult monkey cortex. Journal motor and inhibitory axons. Journal of Neurophysiology 26, of Neuroscience 10, 2438±2450. 739±751. Hendry SHC, Huntsman MM, Vin4 uela A, Mo$ hler H, de Blas Kutay FZ, Po$ gu$ nST , Hariri NI, Peker G, Erlac: in S (1989). Free AL, Jones EG (1994). GABA receptor subunit amino acid level determinations in normal and immunoreactivity in primate visual cortex, distribution in schizophrenic brain. Progress in Neuro-Psychopharmacology macaque and humans and regulation by visual input in and Biological Psychiatry 13, 119±126. adults. Journal of Neuroscience 14, 2383±2401. Lewis DA, Pierri JN, Volk DW, Melchitzky DS, Woo TU Holstein GR, Pasik P, Hamori J (1986). Synapses between (1999). Altered GABA neurotransmission and prefrontal GABA-immunoreactive axonal and dendritic elements in cortical dysfunction in schizophrenia. Biological Psychiatry monkey substantia nigra. Neuroscience Letters 66, 316±322. 46, 616±626. Huffman RD, Ticku MK (1983). The effects of chronic Lewis DA (2000). GABAergic local circuit neurons and haloperidol administration on GABA receptor binding. prefrontal cortical dysfunction in schizophrenia. Brain Pharmacology, Biochemistry and Behavior 19, 199±204. Research Brain Research Reviews 31, 270±276. Huntsman MM, Isackson PJ, Jones EG (1994). Lamina-speci®c Lichtshtein D, Dobkin J, Ebstein RP, Biederman J, Rimon R, expression and activity-dependent regulation of seven Belmaker RH (1978). Gamma-aminobutyric acid (GABA) in GABA receptor subunit mRNA in monkey visual cortex. the CSF of schizophrenic patients before and after Journal of Neuroscience 14, 2236±2259. neuroleptic treatment. British Journal of Psychiatry 132, Huntsman MM, Tran BV, Potkin SG, Bunney Jr. WE, Jones 145±148. EG (1998). Altered ratios of alternatively spliced long and Lund JS, Lewis DA (1993). Local circuit neurons of short c2 subunit mRNAs of the c-amino butyrate type A developing and mature macaque prefrontal cortex, Golgi receptor in prefrontal cortex of schizophrenics. Proceedings and immunocytochemical characteristics. Journal of of the National Academy of Sciences USA 95, 15066±15071. Comparative Neurology 328, 282±312. Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho Luntz-Leybman V, Rotter A, Zdilar D, Frostholm A (1995). H, Pisu MG, Uzunov DP, Smalheiser NR, Davis JM, Uncoupling of GABA }benzodiazepine receptor a , b , " # Pandey GN, Pappas GD, Tueting P, Sharma RP, Costa E and c subunit mRNA expression in cerebellar Purkinje (1998). A decrease of reelin expression as a putative cells of staggerer mutant mice. Journal of Neuroscience 15, vulnerability factor in schizophrenia. Proceedings of the 8121±8130. National Academy of Sciences USA 95, 15718±15723. Manchon M, Kopp N, Rouzioux JJ, Lecestre D, Deluermoz S, Japha K, Koch M (1999). Picrotoxin in the medial prefrontal Miachon S (1987). Benzodiazepine receptor and cortex impairs sensorimotor gating in rats, reversal by neurotransmitter studies in the brain of suicides. Life haloperidol. Psychopharmacology 144, 347±354. Sciences 41, 2623±2630. Jones EG (1990). GABA-peptide neurons in the neocortex McCarthy BW, Gomes UR, Neethling AC, Shanley BC, (` Inhibition in the Brain ' Symposium, November 1986, Taljaard JJ, Potgieter L, Roux JT (1981). c-aminobutyric Washington, DC). In: Paxinos G (Ed.), The Human Brain (p. acid concentration in cerebrospinal ¯uid in schizophrenia. 1116). San Diego : Academic Press. Journal of Neurochemistry 36, 1406±1408. Kalus P, Senitz D, Beckmann H (1997). Altered distribution of McGeer PL, McGeer EG (1976). Enzymes associated with the parvalbumin-immunoreactive local circuit neurons in the metabolism of catecholamines, acetylcholine and GABA in anterior cingulate cortex of schizophrenic patients. human controls and patients with Parkinson's disease and Psychiatry Research, Neuroimaging Section 75, 49±59. Huntington's chorea. Journal of Neurochemistry 26, 65±76. The GABAergic system in schizophrenia 177 McGeer PL, McGeer EG (1977). Possible changes in striatal Perry TL, Hansen S, Gandham SS (1981). Postmortem and limbic cholinergic systems in schizophrenia. Archives of changes of amino compounds in human and rat brain. General Psychiatry 34, 1319±1323. Journal of Neurochemistry 36, 406±412. McGeer PL, McGeer EG, Wada JA (1971). Glutamic acid Perry TL, Hansen S, Jones K (1989). Schizophrenia, tardive decarboxylase in Parkinson's disease and epilepsy. dyskinesia, and brain GABA. Biological Psychiatry 25, Neurology 21, 1000±1007. 200±206. Mizukami K, Sasaki M, Ishikawa M, Iwakiri M, Hidaka S, Perry TL, Kish SJ, Buchanan J, Hansen S (1979). c- Shiraishi H, Iritani S (2000). Immunohistochemical aminobutyric-acid de®ciency in brain of schizophrenic localization of c-aminobutyric acid receptor in the patients. Lancet 1, 237±239. hippocampus of subjects with schizophrenia. Neuroscience Petty F, Sherman AD (1984). Plasma GABA levels in Letters 283, 101±104. psychiatric illness. Journal of Affective Disorders 6, 131±138. Mo$ hler H, Benke D, Fritschy JM, Benson J (2000). The Pierri JN, Chaudry AS, Woo TU, Lewis DA (1999). benzodiazepine site of GABA receptors. In : Martin D, Alterations in chandelier neuron axon terminals in the Olsen R (Eds.), GABA in the Nervous System, The View at prefrontal cortex of schizophrenic subjects. American Journal Fifty Years (pp. 97±112). Philadelphia : Lippincott Williams of Psychiatry 156, 1709±1719. & Wilkins. Reveley MA, Gurling HMD, Glass I, Glover V, Sandler M Moore H, West AR, Grace AA (1999). The regulation of (1980). Platelet c-aminobutyric acid-aminotransferase and forebrain dopamine transmission, relevance to the monoamine oxidase in schizophrenia. Neuropharmacology pathophysiology and psychopathology of schizophrenia. 19, 1249±1250. Biological Psychiatry 46, 40±55. Reynolds GP, Beasley CL (2001). GABAergic neuronal Muly III EC, Szigeti K, Goldman-Rakic PS (1998). D1 receptor subtypes in the human frontal cortex ± development and in interneurons of Macaque prefrontal cortex, distribution de®cits in schizophrenia. Journal of Chemical Neuroanatomy and subcellular distribution. Journal of Neuroscience 18, 22, 95±100. 10553±10565. Reynolds GP, Czudek C, Andrews HB (1990). De®cit and Ohnuma T, Augood SJ, Arai H, McKenna PJ, Emson PC hemispheric asymmetry of GABA uptake sites in the (1999). Measurement of GABAergic parameters in the hippocampus in schizophrenia. Biological Psychiatry 27, prefrontal cortex in schizophrenia, focus on GABA content, 1038±1044. GABA receptor a-1 subunit messenger RNA and human Reynolds GP, Stroud D (1993). Hippocampal benzodiazepine GABA transporter-1 (HGAT-1) messenger RNA receptors in schizophrenia. Journal of Neural Transmission expression. Neuroscience 93, 441±448. (General Section) 93, 151±155. Okada Y, Nitsch-Hassler C, Kim JS, Bak IJ, Hassler R (1971). Rimvall K, Martin DL (1994). The level of GAD67 protein is Role of c-aminobutyric acid (GABA) in the extrapyramidal highly sensitive to small increases in intraneuronal gamma- motor system. 1. Regional distribution of GABA in rabbit, aminobutyric acid levels. Journal of Neurochemistry 62, rat, guinea pig and baboon CNS. Experimental Brain 1375±1381. Research 13, 514±518. Rimvall K, Sheikh SN, Martin DL (1993). Effects of increased Olney JW, Farber NB (1995). Glutamate receptor dysfunction gamma-aminobutyric acid levels on GAD67 protein and and schizophrenia. Archives of General Psychiatry 52, mRNA levels in rat cerebral cortex. Journal of 998±1007. Neurochemistry 60, 714±720. Olsen R, Homanics G (2000). Function of GABA receptors ; Roberts E (1972). An hypothesis suggesting that there is a insights from mutant and knockout mice. In : Martin D, defect in the GABA system in schizophrenia. Neurosciences Olsen R (Eds.), GABA in the Nervous System, The View at Research Program Bulletin 10, 468±481. Fifty Years (pp. 81±96). Philadelphia : Lippincott Williams & Roberts E, Frankel S (1950). c-aminobutyric acid in brain, its Wilkins. formation from glutamic acid. Journal of Biological Chemistry Orkand PM, Kravitz EA (1971). Localization of the sites of c- 187, 55±63. aminobutyric acid (GABA) uptake in lobster nerve-muscle Rochet T, Kopp N, Vedrinne J, Deluermoz S, Debilly G, preparations. Journal of Cell Biology 49, 75±89. Miachon S (1992). Benzodiazepine binding sites and their Otsuka M, Iversen LL, Hall ZW, Kravitz EA (1966). Release modulators in hippocampus of violent suicide victims. of gamma-aminobutyric acid from inhibitory nerves of Biological Psychiatry 32, 922±931. lobster. Proceedings of the National Academy of Sciences USA Schiffer WK, Gerasimov M, Hofmann L, Marsteller D, Ashby 56, 1110±1115. CR, Brodie JD, Alexoff DL, Dewey SL (2001). Gamma Pandey GN, Conley RR, Pandey SC, Goel S, Roberts RC, vinyl-GABA differentially modulates NMDA antagonist- Tamminga CA, Chute D, Smialek J (1997). Benzodiazepine induced increases in mesocortical versus mesolimbic DA receptors in the post-mortem brain of suicide victims and transmission. Neuropsychopharmacology 25, 704±712. schizophrenic subjects. Psychiatry Research 71, 137±149. Schlander M, Thomalske G, Frotscher M (1987). Fine Perry EK, Blessed G, Perry RH, Tomlinson BE (1978). Brain structure of GABAergic neurons and synapses in the biochemistry in schizophrenia. Lancet 1, 35±36. human dentate gyrus. Brain Research 401, 185±189. 178 B. P. Blum and J. J. Mann Spokes EG (1980). Neurochemical alterations in Huntington's Sesack SR, Hawrylak VA, Melchitzky DS, Lewis DA (1998). Dopamine innervation of a subclass of local circuit neurons chorea, a study of post-mortem brain tissue. Brain 103, in monkey prefrontal cortex : ultrastructural analysis of 179±210. tyrosine hydroxylase and parvalbumin immunoreactive Spokes EGS, Garrett NJ, Iversen LL (1979). Differential effects structures. Cerebral Cortex 8, 614±622. of agonal status on measurements of GABA and glutamate Sesack SR, Snyder CL, Lewis DA (1995). Axon terminals decarboxylase in human post-mortem brain tissue from immunolabeled for dopamine or tyrosine hydroxylase control and Huntington's chorea subjects. Journal of synapse on GABA-immunoreactive dendrites in rat and Neurochemistry 33, 773±778. monkey cortex. Journal of Comparative Neurology 363, Spokes EGS, Garrett NJ, Rossor MN, Iversen LL (1980). 264±280. Distribution of GABA in post-mortem brain tissue from Sheikh SN, Martin DL (1998). Elevation of brain GABA levels control, psychotic and Huntington's chorea subjects. Journal with vigabatrin (gamma-vinylGABA) differentially affects of the Neurological Sciences 48, 303±313. GAD65 and GAD67 expression in various regions of rat Squires RF, Lajtha A, Saederup E, Palkovits M (1993). brain. Journal of Neuroscience Research 52, 736±741. Reduced [$H]¯unitrazepam binding in cingulate cortex and Sheikh SN, Martin SB, Martin DL (1999). Regional hippocampus of postmortem schizophrenic brains : is distribution and relative amounts of glutamate selective loss of glutamatergic neurons associated with decarboxylase isoforms in rat and mouse brain. major psychoses? Neurochemical Research 18, 219±223. Neurochemistry International 35, 73±80. Squires RF, Saederup E (1991). A review of evidence for Sherif F, Eriksson L, Oreland L (1992). Gamma-aminobutyrate GABergic predominance}glutamatergic de®cit as a aminotransferase activity in brains of schizophrenic common etiological factor in both schizophrenia and patients. Journal of Neural Transmission (General Section) 90, affective psychoses, more support for a continuum 231±240. hypothesis of ` functional ' psychosis. Neurochemical Research Sherman AD, Davidson AT, Baruah S, Hegwood TS, Waziri 16, 1099±1111. R (1991). Evidence of glutamatergic de®ciency in Sternberg DE (1980). CSF c-aminobutyric acid (GABA) in schizophrenia. Neuroscience Letters 121, 77±80. schizophrenia, Proceedings of the 133rd American Psychiatric Simpson MDC, Royston MC, Slater P, Deakin JFW (1992a). Association, pp. 80±81. Neurochemical abnormalities of the cerebral cortex in Stevens J, Wilson K, Foote W (1974). GABA blockade, schizophrenia. Schizophrenia Research 6, 133±134. dopamine and schizophrenia, experimental studies in the Simpson MDC, Slater P, Deakin JFW (1998a). Comparison of cat. Psychopharmacologia (Berlin) 39, 105±119. glutamate and gamma-aminobutyric acid uptake binding Stevens JR (1999). Epilepsy, schizophrenia, and the extended sites in frontal and temporal lobes in schizophrenia. amygdala. Annals of the New York Academy of Sciences 877, Biological Psychiatry 44, 423±427. Simpson MDC, Slater P, Deak JFW, Gottfries CG, Karlsson I, 548±561. Grenfeldt B, Crow TJ (1998b). Absence of basal ganglia Stocks GM, Cheetham SC, Crompton MR, Katona CL, amino acid neuron de®cits in schizophrenia in three Horton RW (1990). Benzodiazepine binding sites in collections of brains. Schizophrenia Research 31, 167±175. amygdala and hippocampus of depressed suicide victims. Simpson MDC, Slater P, Deakin JFW, Royston MC, Skan WJ Journal of Affective Disorders 18, 11±15. (1989). Reduced GABA uptake sites in the temporal lobe in Stone DJ, Walsh J, Benes FM (1999). Localization of cells schizophrenia. Neuroscience Letter 107, 211±215. preferentially expressing GAD(67) with negligible Simpson MDC, Slater P, Royston MC, Deakin JFW (1992b). GAD(65) transcripts in the rat hippocampus. A double in Regionally selective de®cits in uptake sites for glutamate situ hybridization study. Brain Research Molecular Brain and gamma-aminobutyric acid in the basal ganglia in Research 71, 201±209. schizophrenia. Psychiatry Research 42, 273±282. Todtenkopf MS, Benes FM (1998). Distribution of glutamate Smith Y, Parent A, Seguela P, Descarries L (1987a). decarboxylase immunoreactive puncta on pyramidal and '& Distribution of GABA-immunoreactive neurons in the basal nonpyramidal neurons in hippocampus of schizophrenic ganglia of the squirrel monkey (Saimiri sciureus). Journal of brain. Synapse 29, 323±332. Comparative Neurology 259, 50±64. Toru M, Watanabe S, Shibuya H, Nishikawa T, Noda K, Smith Y, Seguela P, Parent A (1987b). Distribution of GABA- Mitsushio H, Ichikawa H, Kurumaji A, Takashima M, immunoreactive neurons in the thalamus of the squirrel Mataga N, Ogawa A (1988). Neurotransmitters, receptors monkey (Saimiri sciureus). Neuroscience 22, 579±591. and neuropeptides in post-mortem brains of chronic Sorvari H, Soininen H, Paljarvi L, Karkola K, Pitkanen A schizophrenic patients. Acta Psychiatrica Scandinavica 78, (1995). Distribution of parvalbumin-immunoreactive cells 121±137. and ®bers in the human amygdaloid complex. Journal of Udenfriend S (1950). Identi®cation of c-aminobutyric acid in Comparative Neurology 360, 185±212. brain by the isotope derivative method. Journal of Biological Spokes EGS (1979). An analysis of factors in¯uencing Chemistry 187, 65±69. measurements of dopamine, noradrenaline, glutamate van Kammen DP (1979). The dopamine hypothesis of decarboxylase and choline acetylase in human post-mortem schizophrenia revisited. Psychoneuroendocrinology 4, 37±46. brain tissue. Brain 102, 333±346. The GABAergic system in schizophrenia 179 van Kammen DP, Petty F, Kelley ME, Kramer GL, Barry EJ, III WJ, Rose RM (1999). Critical review of GABA-ergic Yao JK, Gurklis JA, Peters JL (1998). GABA and brain drugs in the treatment of schizophrenia. Journal of Clinical abnormalities in schizophrenia. Psychiatry Research, Psychopharmacology 19, 222±232. Neuroimaging Section 82, 25±35. White HL, Davidson JR, Miller RD, Faison LD (1980). Platelet van Kammen DP, Sternberg DE, Hare TA, Waters RN, c-aminobutyrate-a-ketoglutarate transaminase (GABA-T) in Bunney Jr. WE (1982). CSF levels of c-aminobutyric acid in schizophrenia. American Journal of Psychiatry 137, 733±734. schizophrenia. Low values in recently ill patients. Archives Woo TU, Miller JL, Lewis DA (1997). Schizophrenia and the of General Psychiatry 39, 91±97. parvalbumin-containing class of cortical local circuit Vincent SL, Adamec E, Sorensen I, Benes FM (1994). The neurons. American Journal of Psychiatry 154, 1013±1015. effects of chronic haloperidol administration on GABA- Woo TU, Whitehead RE, Melchitzky DS, Lewis DA (1998). A immunoreactive axon terminals in rat medial prefrontal subclass of prefrontal c-aminobutyric acid axon terminals cortex. Synapse 17, 26±35. are selectively altered in schizophrenia. Proceedings of the Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA National Academy of Sciences USA 95, 5341±5346. (2000). Decreased glutamic acid decarboxylase messenger Zander KJ, Fischer B, Zimmer R, Ackenheil M (1981). Long- '( RNA expression in a subset of prefrontal cortical c- term neuroleptic treatment of chronic schizophrenic aminobutyric acid neurons in subjects with schizophrenia. patients, clinical and biochemical effects of withdrawal. Archives of General Psychiatry 57, 237±245. Psychopharmacology 73, 43±47. Volk DW, Austin MC, Pierri JN, Sampson AR, Lewis DA Zimmer R, Teelken AW, Meier KD, Ackenheil M, Zander KJ (2001). GABA transporter-1 mRNA in the prefrontal cortex (1981). Preliminary studies on CSF gamma-aminobutyric in schizophrenia, decreased expression in a subset of acid levels in psychiatric patients before and during neurons. American Journal of Psychiatry 158, 256±265. treatment with different psychotropic drugs. Progress in Wassef AA, Dott SG, Harris A, Brown A, O'Boyle M, Meyer Neuro-Psychopharmacology 4, 613±620.

Journal

International Journal of NeuropsychopharmacologyOxford University Press

Published: Jun 1, 2002

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