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The nuclear factor-κB inhibitor pyrrolidine dithiocarbamate reduces polyinosinic-polycytidilic acid-induced immune response in pregnant rats and the behavioral defects of their adult offspring

The nuclear factor-κB inhibitor pyrrolidine dithiocarbamate reduces polyinosinic-polycytidilic... Background: Epidemiological studies have indicated that maternal infection during pregnancy may lead to a higher incidence of schizophrenia in the offspring. It is assumed that the maternal infection increases the immune response, leading to neurodevelopmental disorders in the offspring. Maternal polyinosinic-polycytidilic acid (PolyI:C) treatment induces a wide range of characteristics in the offspring mimicking some schizophrenia symptoms in humans. These observations are consistent with the neurodevelopmental hypothesis of schizophrenia. Methods: We examined whether suppression of the maternal immune response could prevent neurodevelopmental disorders in adult offspring. PolyI:C or saline was administered to early pregnant rats to mimic maternal infection, and the maternal immune response represented by tumor necrosis factor alpha (TNF-a) and interleukin-10 (IL-10) levels was determined by enzyme-linked immunosorbent assays (ELISA). The NF-B inhibitor pyrrolidine dithiocarbamate (PDTC) was used to suppress the maternal immune response. Neurodevelopmental disorders in adult offspring were examined by prepulse inhibition (PPI), passive avoidance, and active avoidance tests. Results: PolyI:C administration to early pregnant rats led to elevated serum cytokine levels as shown by massive increases in serum TNF-a and IL-10 levels. The adult offspring showed defects in prepulse inhibition, and passive avoidance and active avoidance tests. PDTC intervention in early pregnant rats suppressed cytokine increases and reduced the severity of neurodevelopmental defects in adult offspring. Conclusions: Our findings suggest that PDTC can suppress the maternal immune response induced by PolyI:C and partially prevent neurodevelopmental disorders of adult offspring. Keywords: cytokine, nuclear factor-kappa B inhibitor, prepulse inhibition, passive avoidance, active avoidance Background adult life [1-3]. Early epidemiological data suggested that Epidemiological studies have indicated that maternal maternal infection in the second trimester of human bacterial and viral infections during pregnancy are asso- pregnancy conferred the maximum risk for schizophre- ciated with the emergence of psychosis and related psy- nia in the offspring [4,5]. However, recent studies have chopathology in offspring during post-pubescent or questioned whether the second trimester is exclusively critical [6,7]. Brown et al. [2] showed that infection in the first trimester was also influential. Hence, maternal * Correspondence: lvx928@126.com infections over a more extended period, from early- to † Contributed equally Department of Psychiatry, Henan Mental Hospital, The Second Affiliated mid-pregnancy, can increase the risk of schizophrenia. Hospital of Xinxiang Medical University, Xinxiang, China Full list of author information is available at the end of the article © 2011 Song et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Song et al. Behavioral and Brain Functions 2011, 7:50 Page 2 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 However, it is the maternal immune response, rather Methods than direct infection of the fetus, that leads to increased Chemicals incidence of schizophrenia [8]. Several lines of evidence PolyI:C (potassium salt) and PDTC were obtained from support this hypothesis [9]. First, in addition to their Sigma-Aldrich (Switzerland). PolyI:C was dissolved in immunological roles, pro-inflammatory cytokines have phosphate-buffered saline in 5 mg/ml. PDTC was dis- various neurodevelopmental effects [10]. Second, solved in physiological saline in 100 mg/ml on the day increased maternal levels of the pro-inflammatory cyto- of injection into rats. kine tumor necrosis factor-a (TNF-a)and thechemo- kine interleukin-8 during pregnancy have been directly Animals associated with a higher risk for schizophrenia in the Female and male Sprague-Dawley rats were obtained progeny [11,12]. Third, experiments in animals confirm from a specific-pathogen-free (SPF) breeding colony, that, in the absence of specific pathogens, prenatal expo- about ten weeks old, at the Experimental Animal Cen- sure to cytokine-releasing agents [13-18] is sufficient to ter of Zhengzhou University (Zhengzhou, China). The induce psychopathology in later life. Infection-induced rats came from multiple litters. Littermates of the same elevation of pro-inflammatory cytokines in the maternal sex were caged together with four to five per cage. host may be one of the key events leading to enhanced Breeding began after two weeks of acclimation to the risk of neurodevelopmental disorders in the offspring [19]. new animal holding room. The procedures for breeding Efforts are increasing to develop animal models of and for verification of pregnancy were described by schizophrenia. Although attempts to model human psy- Meyer [13]. All rats were housed in individually venti- chiatric conditions in animals have always been met lated plastic cages at 22 ± 2°C and 50 ± 10% relative with some skepticism, the hypothesized core dysfunc- humidity with a constant day-night cycle (light: 08:00- tions in schizophrenia are amenable to the development 20:00 h). Food and tap water were available ad libitum. of translational models across species–from mice to The Animal Care and Use Committee of the Henan human beings. One recently developed model allows the Key Lab of Biological Psychiatry (Xinxiang, China) link between maternal immune activation (MIA) and approved the use of rats and the experimental proto- the later development of schizophrenia in offspring to cols in this study. be investigated while separating immune activation from maternal infection [20]. This model uses a single sys- Prenatal treatment temic administration of polyinosinic-polycytidilic acid The rats were mated at an age of about 12 weeks. The (PolyI:C) to induce MIA in pregnant animals. Systemic first day after copulation was defined as day 1 of preg- exposure to PolyI:C results in an acutely intense eleva- nancy. Eighty pregnant rats were randomly divided into tion of inflammatory cytokines in the host without the four groups of 20, designated as intervention, model, production of specific antibodies [20-22]. The offspring PDTC, and control groups. On gestation day 9, the rats of PolyI:C treated dames show largely normal behavior in the intervention and model groups were injected as juveniles [17,23,24]. However, once these animals with PolyI:C (5 mg/kg) intravenously through the tail reach adulthood a number of behavioral features of schi- vein. The rats in the intervention group received PDTC zophrenia are evident [18,23-25]. This model is consis- (100 mg/kg) by intraperitoneal injection 30 min prior tent with the neurodevelopmental hypothesis of to PolyI:C injection, followed by PDTC via intraperito- schizophrenia, which posits that maternal infection pro- neal injection and vehicle solution by injection through vokes an immune response leading to neurodevelop- the tail vein. Those in the model group received intra- mental disorders in the offspring. peritoneal injections of physiological saline vehicle The transcription factor nuclear factor-kappa B (NF- solution instead. The rats in the control group received B) regulates genes involved in cell differentiation, sur- two intravenous injections of vehicle solution. The vival/apoptosis, and immune and inflammatory treatments of these four experimental groups are responses [26]. Regulated genes include cytokines, cell showed in Figure 1. In all four groups, half of the rats surface receptors, and antioxidant enzymes. NF-Bcan were retained to fulfill pregnancy; the other rats were increase cytokine levels and amplify the inflammation executed after injection. signal of cytokines by the interaction between cytokines On postnatal day 21, pups were weaned, housed four and NF-B in schizophrenia [27]. Here, we examined to a cage by sex and litter, and maintained undisturbed whether inhibition of NF-Bcould suppress the until three months of age. One of each littermates was immune response induced by PolyI:C treatment of preg- randomly selected for behavioral testing. The number of nant rats and thereby reduce neurodevelopmental disor- subjects employed in the behavioral testing is summar- ders in the adult offspring. ized in Table 1. Song et al. Behavioral and Brain Functions 2011, 7:50 Page 3 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 PDTC+PolyI:C saline+saline PDTC+saline saline+PolyI:C Control group PDTC group Model group Intervention group Figure 1 The treatments of the four experimental groups. Cytokine and NF-B activation assay behavioral response, immediately precedes an unex- Blood samples were taken from the orbital sinus of rats pected stronger startling stimulus. PPI was determined under methoxyflurane (2,2-dichloro-1,1-difluoro-1- by measuring the decrement in the startle response methoxyethane; Pitman-Moore, Titusville, NJ) anesthesia when the acoustic startle-eliciting stimulus was preceded three hours after rats were injected with PolyI:C. by an auditory or visual prepulse (PP). The amount of Approximately 1 ml of blood per animal was collected. PPI is expressed as the percentage decrease in the The blood from each animal was separated into serum amplitude of the startle response caused by presentation and white blood cell fractions. of the prepulse. The serum was divided into two parts to permit sto- All test sessions were performed in a single chamber rage at -80°C until the cytokine assay was performed. startle apparatus (QMC-I, Kunming Institute of Zoology, IL-10 and TNF-a levels were evaluated using an ELISA Chinese Academy of Sciences, China). One rat was kit (R&D Systems) according to the manufacturer’s tested during each experimental session. The rat was recommendations. The detection limits for IL-10 and accommodated in a nonrestrictive Plexiglas cylinder (9 TNF-a were 10.0 and 5.0 pg/mL, respectively, with cm diameter, 18.5 cm long) mounted on a floor plate inter-assay variation coefficients of 9.9% and 9.7% and inside a sound- and vibration-attenuating cabinet intra-assay variation coefficients of 4.6% and 5.1%, equipped with a 15 W incandescent bulb and a fan for respectively. Standard curve concentrations were calcu- ventilation. A piezoelectric accelerometer was attached lated in triplicate for each plate. beneath the floor plate to detect and transduce the rat’s Nuclear proteins were extracted from peripheral blood motor response. A computer program delivered white mononuclear cells (PBMC) using a Nuclear Extract Kit noise stimuli via an amplifier and a speaker mounted in (Active Motif, Carlsbad, California) according to the the chamber above the cylinder. At a rate of 1,000 Hz, manufacturer’s instructions. Extracts were stored at 80° the computer sampled accelerometer signals from 200 C until assayed for the activation of transcription factor ms before each acoustic stimulus to 2,300 ms after an NF-B. acoustic stimulus was delivered. The rats were moni- Activation of the NF-B p65 subunit was determined tored by a video monitoring system during each test. using an NF-B p65 ELISA-based transcription factor In the test session, the rats were acclimated in the assay kit (TransAM assay; Active Motif) according to testing cylinder for five minutes, during which the rats the manufacturer’sprotocol[28,29].The NF-Bdetec- received only background noiseof70 dBSPL. Thetest tion antibody recognizes an epitope on p65 that is began with six trials of a pulse-alone startle stimulus, accessible only when NF-B is activated. The detection consisting of a 40 ms burst of white noise of 120 dB limit was 0.4 ng recombinant p50 protein per well. SPL. The session continued with 20 randomized trials, which included five trials of a pulse-alone stimulus and Prepulse inhibition (PPI) testing five trials for each of three types of prepulse startles. A PPI is the normal suppression of a startle response when prepulse startleconsisted of aprepulse(whitenoiseat a low intensity stimulus, which elicits little or no 2, 4 or 8 dB SPL above the 70 dB SPL background), a Table 1 Sample size of each treatment group and experimental condition, and the sequence of behavioral testing Experiments Control PDTC Prenatal Poly(I:C) treatment(5 mg/kg) PDTC (100 mg/kg) Vehicle Prepulse inhibition 5♀7♂ 6♀5♂ 5♀5♂ 5♀5♂ Passive avoidance 6♀5♂ 5♀6♂ 6♀5♂ 4♀5♂ Active avoidance procedure 5♀5♂ 6♀5♂ 5♀5♂ 5♀6♂ Song et al. Behavioral and Brain Functions 2011, 7:50 Page 4 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 100 ms interval, and a startle pulse (40 ms, 120 dB SPL stimulus (US), an electric shock (0.3 mA) continuously white noise). The interval length between the 20 rando- applied to through the floor, associated with the presen- mized trials varied randomly from 8 to 23 s with an tation of a light (10 W), which served as a conditioned average of 15 s. stimulus (CS). The shuttle box had two compartments Startle responses were measured with the program (20 × 10 cm) connected by a 3 × 3 cm door. In the developed by Kunming Institute of Zoology, Chinese compartment containing the mouse, the CS was pre- Academy of Sciences, China. The peak value of the sented for 5 s followed by concurrent presentation of motor response between auditory stimuli onset and the CS and US for 25 s. At the end of the 30-s (total) 1,000 ms was automatically analyzed for each trial and period, the CS and the US were automatically turned the average response was calculated for each type of sti- off. A conditioned response was recorded when the ani- mulus. The amount of prepulse inhibition (PPI) was mal avoided the US by moving to the empty compart- expressed as the percentage decrease in the amplitude ment within 5 s of the onset of the CS. If animals failed of the startle response caused by presentation of the to avoid the shock, they could escape it by crossing dur- prepulse. The amplitude of the startle response without ing the US (25 s). Between each trial, there was an inter- a prepulse is p. When a weak stimulus is given prior to val of 30 s. The ratio of conditioned responses with the startle reflex stimulus, the amplitude for the startle respect to the total number of changes of compartment response is pp. The percentage of PPI for each rat was was also determined. calculated as (1-pp/p) × 100, which is proportional to The rats received 100 trials per day for 5 consecutive the inhibitory effect of PPI. Using this description of days [30]. Before the start of each session of trials, the PPI, a high degree of sensorimotor gating is reflected in rats were placed in the shuttle box for 10 min and a high % PPI value, whereas lower or no gating results allowed to explore. The final rate of active avoidance in a small or negative % PPI value. conditioned response was calculated as (total number of condition responses/500). Higher values indicated better Passive Avoidance Test learning and memory. The passive avoidance test is a fear-aggravated test used to assess short-term or long-term memory on small Data analysis laboratory animals. In this test, subjects learn to avoid Data analyses were conducted using SPSS 13.0 for Win- an environment in which an aversive stimulus (such as dows. Test results were presented as means ± standard a foot-shock) was previously delivered. The recent mem- deviations (SD). Cytokine data were analyzed using one- ory of the rats was tested in a passive avoidance-condi- way analysis of variance (ANOVA). Active avoidance tioning task. Two days after evaluation of general motor and passive avoidance test data were analyzed using activity, learning was evaluated in a single trial, passive repeated-measures ANOVA. PPI data were analyzed avoidance test. The conditioning and testing apparatus using multivariate analysis of variance (MANOVA) fol- consisted of a shuttle box (Ugo Basile model 7550, lowed by least significant difference (LSD) post hoc Comerio, Italy) equipped with a door to restrict access pair-wise comparisons for analysis of differences between illuminated and dark compartments of equal between groups. Bonferroni corrections were performed size. In the acquisition trial, a rat was placed in the illu- for multiple tests. minated compartment. After 30 s, the door separating the two compartments was opened. Some seconds later Results (T1), the animal spontaneously entered the dark com- Exposure of maternal rats to PolyI:C significantly partment. The door was shut 1 s after the crossing, and increased IL-10 and TNF-a protein levels in the mater- the rat was given a 0.5 mA, 3 s duration foot shock. nal serum (Table 2). Treatment effects were evident 3 h Twenty-four hours later (retention trial), the same pro- after exposure. Intervention with PDTC partially sup- cedure was repeated without a delay period to open the pressed the increase in cytokine levels. Rats treated only door and without an electric shock. The elapsed time to with PDTC showed no effects relative to control-treated enter the dark compartment was recorded as T2. rats. NF-B activation in maternal PBMC is not shown because it was below the detection limit. Active Avoidance Test To determine whether adult offspring from mothers The active avoidance task is a fear-motivated associative with different treatments have PPI defects, PP2, PP4, avoidance test based on electric current as a source of and PP8 were designated according to the decibel value punishment. This task provides a simple way to assess of prepulse startle stimuli (respectively 2, 4 or 8 dB SPL associative learning and memory of laboratory animals. above the 70 dB SPL background). As expected, the In a two-way shuttle box apparatus (Panlab, Barcelona), level of prepulse inhibition increased with increasing the rats were trained to avoid an aversive unconditioned prepulse intensity for all treatment groups. Multi-factor Song et al. Behavioral and Brain Functions 2011, 7:50 Page 5 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 Table 2 Serum Levels of IL-10 and TNF-a in animals Control group PDTC Group Model group Intervention group FP a, b a, b b IL-10(pg/mL) 0.19 ± 0.09 0.15 ± 0.09 19.14 ± 2.21 13.67 ± 0.97 632.049 < 0.001 a, b a, b b TNF-a(pg/mL) 11.96 ± 1.81 9.22 ± 3.00 128.48 ± 10.38 33.19 ± 2.91 983.570 < 0.001 a b One-way analysis of variance was used, P < 0.05. compared with model group, P < 0.05; compared with intervention group, P < 0.05. (treatment×prepulse intensities) ANOVA of %PPI group (P = 0.04). For the intervention group, this defect revealed a significant treatment effect (F = 58.867, P < was improved from the model group in both T1 (P = 0.001) (Figure 2). While the PDTC group did not differ 0.004) and T2 (P = 0.014). These results demonstrate from the control group, offspring from mothers injected improvements by PDTC treatment on memory impair- with PolyI:C exhibited significantly reduced %PPI relative ment in adult offspring from pregnant rats exposed to to controls (P < 0.05). The offspring from mothers trea- PolyI:C. ted with PolyI:C and PDTC had a higher %PPI (P < 0.05) Maternal exposure to PolyI:C significantly reduced the than the rats born to mothers treated with only PolyI:C. performance of adult offspring in an active avoidance Maternal exposure to PolyI:C significantly enhance PPI task (Figure 4). The offspring showed fewer conditioned defects of adult offspring, and this effect can be weakened responses compared to controls from the first training by treatment with PDTC after exposure. session. The performance deficit in offspring was PDTC treatment displays significant effect on the per- reduced by treatment of pregnant rats with PDTC after formance reduction of the adult offspring from maternal exposure to PolyI:C. Repeated measures ANOVA exposure to PolyI:C in a passive avoidance task (Figure revealed a significant main effect of day of training (F = 3). ANOVA showed a significant treatment effect (F = 434.264, P < 0.001), a significant effect of the treatment 135.010, P < 0.001). Offspring from the model group (F = 17.222, P < 0.001), and a significant interaction (mothers treated with only PolyI:C) had a longer T1 between these two factors (F = 6.934, P < 0.001). than offspring from the control group (P < 0.001), as Total conditioned response times were significantly different among offspring from the four treatment well as a shorter T2 than offspring from the control Control Group PDTC Group Model Group Intervention Group PP2 PP4 PP8 Figure 2 The effects of PDTC in prenatal PolyI:C administration on PPI of the adult offspring. PP2, PP4, and PP8 were designated according to the intensity of the prepulse (i.e., 2, 4 or 8 dB SPL above the 70 dB SPL background). Multivariate analysis of variance was used, LSD examination was used for Post hoc analysis, compared with control group, *P < 0.05; compared with intervention group, P < 0.05. Percent Prep ulse Inhibition Song et al. Behavioral and Brain Functions 2011, 7:50 Page 6 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 Control Group PDTC group Model Group Intervention Group T1 T2 Figure 3 The effects of PDTC in prenatal PolyI:C administration on passive avoidance behavior of the adult offspring. Acquisition (T1) and retention 24 h later (T2) were recorded. Multivariate analysis of variance was used, LSD examination was used for Post hoc analysis, compared with control group, *P < 0.05; compared with intervention group, P < 0.05. Control Group PDTC Group Model Group Intervention Group D1 D2 D3 D4 D5 Figure 4 The effects of PDTC in prenatal PolyI:C administration on active avoidance behavior of the adult offspring. The average number of conditioned changes in a shuttle box testing apparatus was recorded. Repeated measures ANOVA analysis of variance was used, compared among four groups, *P < 0.05. Number of Conditioned Changes Acquition(T1)/Retention 24h later(T2) Song et al. Behavioral and Brain Functions 2011, 7:50 Page 7 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 Table 3 Active avoidance of adult offspring ( x¯ ± s ) Control group PDTC Group Model group Intervention group ab ab Total reflex times 285.9 ± 42.36 279.36 ± 38.19 182.00 ± 21.97 205.00 ± 52.45 ab ab Total reflex rate 0.57 ± 0.085 0.56 ± 0.076 0.36 ± 0.043 0.41 ± 0.105 a b One-way analysis of variance was used, P < 0.05. compared with model group, P < 0.05; compared with intervention group, P < 0.05. groups (F = 17.22, P < 0.001; one-way ANOVA) (Table above indicated that PDTC, a kind of NF-B inhibitor, 3). The average reflex time was higher for the control can interfere with the inflammatory reactions mediated group than intervention and model groups (P <0.001 by cytokines. for both). No statistical difference was found between Behavioral deficits occurred in offspring from mother intervention group and model group. There were signifi- rats that had an immune response induced by PolyI:C cant differences in total response rates among offspring treatment. The offspring of the model group showed from thefourgroups; theratewas higher inoffspring weakened PPI and weakened latent inhibition. These from the control group compared to the intervention findings are consistent with Meyer [13], who reported and model groups (P = 0.002, P < 0.001). No statistical that administration of PolyI:C to pregnant mice led to a difference was found between the intervention group loss of PPI, loss of latent inhibition, and multiple schizo- and the model group. phrenia-like neuropathologic manifestations in the off- spring. Behavioral abnormalities were less severe in Discussion offspring from the intervention group compared to Both epidemiological and animal experimental studies offspring from the model group, demonstrating that have demonstrated that during early pregnancy, mater- inhibition of NF-B during pregnancy reduced neurode- nal immune response mediated by pro-inflammatory velopmental disorders in the offspring. cytokines is associated with higher risk for neuropsy- Latent inhibition exists in all classical and instrumen- chiatric disorders in the offspring [31,32]. It was tal conditioned reflexes, such as passive and active avoidance. Baruch et al. [37] first reported latent inhibi- reported that the NF-B inhibitor, which blocked the tion loss in schizophrenia patients, finding that acute NF-B signaling pathway and reduced cytokine release, was effective in many related diseases [33-35]. In this schizophrenic patients lost latent inhibition, while study, PolyI:C was administered to rats in early preg- chronic patients treated with antipsychotics presented nancy to stimulate the release of pro-inflammatory cyto- with normal latent inhibition. Several clinical studies kines. Maternal cytokine levels and the behavior of adult [38-40] further supported this result. Salgado [41] offspring were measured to explore the role of the cyto- reported that the dopamine antagonist amphetamine kine-mediated immune response during pregnancy in could cause loss of latent inhibition in normal healthy the development of psychiatric disorders. We also exam- people, and conversely, antipsychotics could enhance ined the effects of intervention with an NF-B inhibitor, latent inhibition. Similar results occurred in animals PDTC. [42]. In addition, individuals from schizophrenic parents In this study, serum levels of IL-10 and TNF-a in the showed abnormal latent inhibition. These studies model group (pregnant rats treated with PolyI:C) showed that abnormal latent inhibition in patients with increased significantly compared to levels in the control schizophrenia could be regarded as a stable manifesta- group. This imitated inflammatory reactions mediated tion and a cognitive deficit in behavior. In active avoid- by cytokines in maternal hosts after infection. Gayle et ance tests, the total conditioned reflex time in offspring al. [36] reported that PolyI:C, as well as LPS, could from the control group was significantly higher than in increase the cytokine level in the amniotic fluid and the the offspring from model group (PolyI:C-treated), imply- placenta of the maternal host. Increased cytokines could ing that latent inhibition abnormality, impaired learning, enter the circulatory system of the fetus. and impaired memory occurred in offspring from model group. In passive avoidance tests, the T1 and T2 in In our previous study, schizophrenic patients showed model group offspring were also significantly different activation of NF-B and elevated levels of cytokines from those in control group offspring, indicating that [27]. In the present study, activated NF-Bwas below the detection limit in our assays. In the intervention memory was impaired. These results are consistent with group, NF-B activation was inhibited through injection previous studies [13-15]. In the active avoidance test, a of PDTC and serum levels of IL-10 and TNF-a were significant effect of the treatment was found. However, suppressed relative to the model group. These results for total conditioned response times, the performance of provide indirect evidence that NF-B activation was suc- offspring from the intervention group and model group cessfully reduced in the intervention group. All the were not significantly different, demonstrating that NF- Song et al. Behavioral and Brain Functions 2011, 7:50 Page 8 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 activation; NF-κB: Nuclear factor-kappa B; US: unconditioned stimulus; CS: B inhibition did not improve all behavioral outcomes conditioned stimulus; LSD: least significant difference; PBMC: peripheral in offspring from the intervention group. blood mononuclear cell; PPI: prepulse inhibition. The neurodevelopmental hypothesis of schizophrenia Acknowledgements posits a correlation between the disease and neurodeve- Funding for this study was provided by the National Natural Science lopmental disorders. It has been suggested that the Foundation of China (30971058 to X-QS; 81071090, 30870892 to L-XL), the maternal immune response to viral infections in preg- Natural Science Foundation of Henan (102300413208, 112300413226 to L- XL), the Program for Innovative Research Team (in Science and Technology) nancy may interfere with normal fetal brain develop- in University of Henan Province (2008IRTSTHN008 to L-XL); the Youth Fund ment. Motivated by this hypothesis, researchers have of the First Affiliated Hospital of Zhenzhou University (to X-QS). created many animal models to study the effects of pre- Author details natal and perinatal environments on schizophrenia. Department of Psychiatry, The First Affiliated Hospital of Zhengzhou Meyer [13] et al. reported that the PolyI:C treatment University, Zhengzhou, China. Department of Psychiatry, Henan Mental model in rats shared a wide range of characteristics with Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China. Henan Key Lab of Biological Psychiatry, Xinxiang Medical humans, and PolyI:C treatment effects manifested in University, Xinxiang, China. The Mental Health Institute of the Second post-pubescent offspring were consistent with the neural Xiangya Hospital, Central South University, Changsha, China. development hypothesis. We demonstrated that prenatal Authors’ contributions treatment with PolyI:C could elevate maternal cytokines LL and XS participated in the design of the study and made final approval and cause reduced PPI and reduced latent inhibition in of the version to be published. XS and WL were involved in drafting the adult offspring, confirming Meyer’s results. Current stu- manuscript and data analysis. CJ, YY and WL carried out the animal experiment JZ undertook revise the manuscript. All authors read and dies concentrate on cytokines as a neurodevelopmental approved the final manuscript. disorder trigger in maternal hosts after infection. Pro- inflammatory cytokines released by the maternal Competing interests The authors declare that they have no competing interests. immune system may disrupt fetal brain development. Transfer of maternal cytokines to fetuses is not the only Received: 23 August 2011 Accepted: 31 December 2011 means of elevating cytokine levels in fetal brains [43]; Published: 31 December 2011 the response of fetal immune systems to increased References maternal cytokines might be an alternate mechanism 1. Brown AS, Schaefer CA, Wyatt RJ, Goetz R, Begg MD, Gorman JM, Susser ES: [43]. The influence of enhanced anti-inflammatory cyto- Maternal exposure to respiratory infections and adult schizophrenia kine signaling on early brain development should be spectrum disorders: a prospective birth cohort study. 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Patterson PH: Maternal infection: window on neuroimmune interactions of offspring. The exact mechanism needs further study. in fetal brain development and mental illness. Curr Opin Neurobiol 2002, 12(1):115-8. 9. Smith SE, Li J, Garbett K, Mirnics K, Patterson PH: Maternal Immune Conclusions Activation Alters Fetal Brain Development through Interleukin-6. J Our findings suggest that PDTC treatment during preg- Neurosci 2007, 27(40):10695-702. 10. Gilmore JH, Fredrik Jarskog L, Vadlamudi S, Lauder JM: Prenatal infection nancy can partially reduce neurodevelopmental disor- and risk for schizophrenia: IL-1beta, IL-6, and TNFalpha inhibit cortical ders of adult offspring by suppressing the maternal neuron dendrite development. Neuropsychopharmacology 2004, immune response induced by PolyI:C. 29(7):1221-9. 11. Brown AS, Hooton J, Schaefer CA, Zhang H, Petkova E, Babulas V, Perrin M, Gorman JM, Susser ES: Elevated maternal interleukin-8 levels and risk of List of abbreviations schizophrenia in adult offspring. Am J Psychiatry 2004, 161(5):889-95. PolyI:C: polyinosinic-polycytidilic acid; TNF-α: necrosis factor alpha; IL-10: 12. Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Wagner RL, Yolken RH: interleukin-10; ELISA: enzyme-linked immunosorbent assay; PDTC: Maternal cytokine levels during pregnancy and adult psychosis. Brain pyrrolidinedithiocarbamate; PPI: prepulse inhibition; MIA: maternal immune Behav Immun 2001, 15(4):411-20. Song et al. Behavioral and Brain Functions 2011, 7:50 Page 9 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 13. Meyer U, Feldon J, Schedlowski M, Yee BK: Towards an immuno- kappaB in a context-dependent manner. J Biol Chem 2010, precipitated neurodevelopmental animal model of schizophrenia. 285(21):15746-52. 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J Haddad JJ, Saadé NE, Safieh-Garabedian B: Cytokines and neuro- 23. Zuckerman L, Rehavi M, Nachman R, Weiner I: Immune activation during immune-endocrine interactions: a role for the hypothalamic-pituitary- pregnancy in rats leads to a postpubertal emergence of disrupted latent adrenal revolving axis. J Neuroimmunol 2002, 133(1-2):1-19. inhibition, dopaminergic hyperfunction, and altered limbic morphology doi:10.1186/1744-9081-7-50 in the offspring: a novel neurodevelopmental model of schizophrenia. Cite this article as: Song et al.: The nuclear factor-B inhibitor Neuropsychopharmacology 2003, 28(10):1778-89. pyrrolidine dithiocarbamate reduces polyinosinic-polycytidilic acid- 24. Zuckerman L, Weiner I: Post-pubertal emergence of disrupted latent induced immune response in pregnant rats and the behavioral defects inhibition following prenatal immune activation. Psychopharmacology of their adult offspring. Behavioral and Brain Functions 2011 7:50. (Berl) 2003, 169(3-4):308-13. 25. Shi L, Fatemi SH, Sidwell RW, Patterson PH: Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 2003, 23(1):297-302. 26. Baeuerle PA: The inducible transcription activator NF-kappa B: regulation by distinct protein subunits. Biochim Biophys Acta 1991, 1072(1):63-80. 27. Song XQ, Lv LX, Li WQ, Hao YH, Zhao JP: The Interaction of Nuclear Factor-Kappa B and Cytokines Is Associated with Schizophrenia. Biol Psychiatry 2009, 65(6):481-8. 28. O’Hara AM, O’Regan P, Fanning A, O’Mahony C, Macsharry J, Lyons A, Bienenstock J, O’Mahony L, Shanahan F: Functional modulation of human intestinal epithelial cell responses by Bifidobacterium infantis and Lactobacillus salivarius. Immunology 2006, 118(2):202-15. 29. Renard P, Ernest I, Houbion A, Art M, Le Calvez H, Raes M, Remacle J: Development of a sensitive multi-well colorimetric assay for active NFκB. Nucleic Acids Res 2001, 29(4):E21. 30. Trigo JM, Cabrero-Castel A, Berrendero F, Maldonado R, Robledo P: MDMA Submit your next manuscript to BioMed Central modifies active avoidance learning and recall in mice. and take full advantage of: Psychopharmacology (Berl) 2008, 197(3):391-400. 31. Meyer U, Nyffeler M, Schwendener S, Knuesel I, Yee BK, Feldon J: Relative • Convenient online submission prenatal and postnatal maternal contributions to schizophrenia-related neurochemical dysfunction after in utero immune challenge. • Thorough peer review Neuropsychopharmacology 2008, 33(2):441-56. • No space constraints or color figure charges 32. Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J: Adult brain and • Immediate publication on acceptance behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun • Inclusion in PubMed, CAS, Scopus and Google Scholar 2008, 22(4):469-86. • Research which is freely available for redistribution 33. Loukili N, Rosenblatt-Velin N, Rolli J, Levrand S, Feihl F, Waeber B, Pacher P, Liaudet L: Oxidants positively or negatively regulate nuclear factor Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

The nuclear factor-κB inhibitor pyrrolidine dithiocarbamate reduces polyinosinic-polycytidilic acid-induced immune response in pregnant rats and the behavioral defects of their adult offspring

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Springer Journals
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Copyright © 2011 by Song et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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1744-9081
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10.1186/1744-9081-7-50
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22208616
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Abstract

Background: Epidemiological studies have indicated that maternal infection during pregnancy may lead to a higher incidence of schizophrenia in the offspring. It is assumed that the maternal infection increases the immune response, leading to neurodevelopmental disorders in the offspring. Maternal polyinosinic-polycytidilic acid (PolyI:C) treatment induces a wide range of characteristics in the offspring mimicking some schizophrenia symptoms in humans. These observations are consistent with the neurodevelopmental hypothesis of schizophrenia. Methods: We examined whether suppression of the maternal immune response could prevent neurodevelopmental disorders in adult offspring. PolyI:C or saline was administered to early pregnant rats to mimic maternal infection, and the maternal immune response represented by tumor necrosis factor alpha (TNF-a) and interleukin-10 (IL-10) levels was determined by enzyme-linked immunosorbent assays (ELISA). The NF-B inhibitor pyrrolidine dithiocarbamate (PDTC) was used to suppress the maternal immune response. Neurodevelopmental disorders in adult offspring were examined by prepulse inhibition (PPI), passive avoidance, and active avoidance tests. Results: PolyI:C administration to early pregnant rats led to elevated serum cytokine levels as shown by massive increases in serum TNF-a and IL-10 levels. The adult offspring showed defects in prepulse inhibition, and passive avoidance and active avoidance tests. PDTC intervention in early pregnant rats suppressed cytokine increases and reduced the severity of neurodevelopmental defects in adult offspring. Conclusions: Our findings suggest that PDTC can suppress the maternal immune response induced by PolyI:C and partially prevent neurodevelopmental disorders of adult offspring. Keywords: cytokine, nuclear factor-kappa B inhibitor, prepulse inhibition, passive avoidance, active avoidance Background adult life [1-3]. Early epidemiological data suggested that Epidemiological studies have indicated that maternal maternal infection in the second trimester of human bacterial and viral infections during pregnancy are asso- pregnancy conferred the maximum risk for schizophre- ciated with the emergence of psychosis and related psy- nia in the offspring [4,5]. However, recent studies have chopathology in offspring during post-pubescent or questioned whether the second trimester is exclusively critical [6,7]. Brown et al. [2] showed that infection in the first trimester was also influential. Hence, maternal * Correspondence: lvx928@126.com infections over a more extended period, from early- to † Contributed equally Department of Psychiatry, Henan Mental Hospital, The Second Affiliated mid-pregnancy, can increase the risk of schizophrenia. Hospital of Xinxiang Medical University, Xinxiang, China Full list of author information is available at the end of the article © 2011 Song et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Song et al. Behavioral and Brain Functions 2011, 7:50 Page 2 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 However, it is the maternal immune response, rather Methods than direct infection of the fetus, that leads to increased Chemicals incidence of schizophrenia [8]. Several lines of evidence PolyI:C (potassium salt) and PDTC were obtained from support this hypothesis [9]. First, in addition to their Sigma-Aldrich (Switzerland). PolyI:C was dissolved in immunological roles, pro-inflammatory cytokines have phosphate-buffered saline in 5 mg/ml. PDTC was dis- various neurodevelopmental effects [10]. Second, solved in physiological saline in 100 mg/ml on the day increased maternal levels of the pro-inflammatory cyto- of injection into rats. kine tumor necrosis factor-a (TNF-a)and thechemo- kine interleukin-8 during pregnancy have been directly Animals associated with a higher risk for schizophrenia in the Female and male Sprague-Dawley rats were obtained progeny [11,12]. Third, experiments in animals confirm from a specific-pathogen-free (SPF) breeding colony, that, in the absence of specific pathogens, prenatal expo- about ten weeks old, at the Experimental Animal Cen- sure to cytokine-releasing agents [13-18] is sufficient to ter of Zhengzhou University (Zhengzhou, China). The induce psychopathology in later life. Infection-induced rats came from multiple litters. Littermates of the same elevation of pro-inflammatory cytokines in the maternal sex were caged together with four to five per cage. host may be one of the key events leading to enhanced Breeding began after two weeks of acclimation to the risk of neurodevelopmental disorders in the offspring [19]. new animal holding room. The procedures for breeding Efforts are increasing to develop animal models of and for verification of pregnancy were described by schizophrenia. Although attempts to model human psy- Meyer [13]. All rats were housed in individually venti- chiatric conditions in animals have always been met lated plastic cages at 22 ± 2°C and 50 ± 10% relative with some skepticism, the hypothesized core dysfunc- humidity with a constant day-night cycle (light: 08:00- tions in schizophrenia are amenable to the development 20:00 h). Food and tap water were available ad libitum. of translational models across species–from mice to The Animal Care and Use Committee of the Henan human beings. One recently developed model allows the Key Lab of Biological Psychiatry (Xinxiang, China) link between maternal immune activation (MIA) and approved the use of rats and the experimental proto- the later development of schizophrenia in offspring to cols in this study. be investigated while separating immune activation from maternal infection [20]. This model uses a single sys- Prenatal treatment temic administration of polyinosinic-polycytidilic acid The rats were mated at an age of about 12 weeks. The (PolyI:C) to induce MIA in pregnant animals. Systemic first day after copulation was defined as day 1 of preg- exposure to PolyI:C results in an acutely intense eleva- nancy. Eighty pregnant rats were randomly divided into tion of inflammatory cytokines in the host without the four groups of 20, designated as intervention, model, production of specific antibodies [20-22]. The offspring PDTC, and control groups. On gestation day 9, the rats of PolyI:C treated dames show largely normal behavior in the intervention and model groups were injected as juveniles [17,23,24]. However, once these animals with PolyI:C (5 mg/kg) intravenously through the tail reach adulthood a number of behavioral features of schi- vein. The rats in the intervention group received PDTC zophrenia are evident [18,23-25]. This model is consis- (100 mg/kg) by intraperitoneal injection 30 min prior tent with the neurodevelopmental hypothesis of to PolyI:C injection, followed by PDTC via intraperito- schizophrenia, which posits that maternal infection pro- neal injection and vehicle solution by injection through vokes an immune response leading to neurodevelop- the tail vein. Those in the model group received intra- mental disorders in the offspring. peritoneal injections of physiological saline vehicle The transcription factor nuclear factor-kappa B (NF- solution instead. The rats in the control group received B) regulates genes involved in cell differentiation, sur- two intravenous injections of vehicle solution. The vival/apoptosis, and immune and inflammatory treatments of these four experimental groups are responses [26]. Regulated genes include cytokines, cell showed in Figure 1. In all four groups, half of the rats surface receptors, and antioxidant enzymes. NF-Bcan were retained to fulfill pregnancy; the other rats were increase cytokine levels and amplify the inflammation executed after injection. signal of cytokines by the interaction between cytokines On postnatal day 21, pups were weaned, housed four and NF-B in schizophrenia [27]. Here, we examined to a cage by sex and litter, and maintained undisturbed whether inhibition of NF-Bcould suppress the until three months of age. One of each littermates was immune response induced by PolyI:C treatment of preg- randomly selected for behavioral testing. The number of nant rats and thereby reduce neurodevelopmental disor- subjects employed in the behavioral testing is summar- ders in the adult offspring. ized in Table 1. Song et al. Behavioral and Brain Functions 2011, 7:50 Page 3 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 PDTC+PolyI:C saline+saline PDTC+saline saline+PolyI:C Control group PDTC group Model group Intervention group Figure 1 The treatments of the four experimental groups. Cytokine and NF-B activation assay behavioral response, immediately precedes an unex- Blood samples were taken from the orbital sinus of rats pected stronger startling stimulus. PPI was determined under methoxyflurane (2,2-dichloro-1,1-difluoro-1- by measuring the decrement in the startle response methoxyethane; Pitman-Moore, Titusville, NJ) anesthesia when the acoustic startle-eliciting stimulus was preceded three hours after rats were injected with PolyI:C. by an auditory or visual prepulse (PP). The amount of Approximately 1 ml of blood per animal was collected. PPI is expressed as the percentage decrease in the The blood from each animal was separated into serum amplitude of the startle response caused by presentation and white blood cell fractions. of the prepulse. The serum was divided into two parts to permit sto- All test sessions were performed in a single chamber rage at -80°C until the cytokine assay was performed. startle apparatus (QMC-I, Kunming Institute of Zoology, IL-10 and TNF-a levels were evaluated using an ELISA Chinese Academy of Sciences, China). One rat was kit (R&D Systems) according to the manufacturer’s tested during each experimental session. The rat was recommendations. The detection limits for IL-10 and accommodated in a nonrestrictive Plexiglas cylinder (9 TNF-a were 10.0 and 5.0 pg/mL, respectively, with cm diameter, 18.5 cm long) mounted on a floor plate inter-assay variation coefficients of 9.9% and 9.7% and inside a sound- and vibration-attenuating cabinet intra-assay variation coefficients of 4.6% and 5.1%, equipped with a 15 W incandescent bulb and a fan for respectively. Standard curve concentrations were calcu- ventilation. A piezoelectric accelerometer was attached lated in triplicate for each plate. beneath the floor plate to detect and transduce the rat’s Nuclear proteins were extracted from peripheral blood motor response. A computer program delivered white mononuclear cells (PBMC) using a Nuclear Extract Kit noise stimuli via an amplifier and a speaker mounted in (Active Motif, Carlsbad, California) according to the the chamber above the cylinder. At a rate of 1,000 Hz, manufacturer’s instructions. Extracts were stored at 80° the computer sampled accelerometer signals from 200 C until assayed for the activation of transcription factor ms before each acoustic stimulus to 2,300 ms after an NF-B. acoustic stimulus was delivered. The rats were moni- Activation of the NF-B p65 subunit was determined tored by a video monitoring system during each test. using an NF-B p65 ELISA-based transcription factor In the test session, the rats were acclimated in the assay kit (TransAM assay; Active Motif) according to testing cylinder for five minutes, during which the rats the manufacturer’sprotocol[28,29].The NF-Bdetec- received only background noiseof70 dBSPL. Thetest tion antibody recognizes an epitope on p65 that is began with six trials of a pulse-alone startle stimulus, accessible only when NF-B is activated. The detection consisting of a 40 ms burst of white noise of 120 dB limit was 0.4 ng recombinant p50 protein per well. SPL. The session continued with 20 randomized trials, which included five trials of a pulse-alone stimulus and Prepulse inhibition (PPI) testing five trials for each of three types of prepulse startles. A PPI is the normal suppression of a startle response when prepulse startleconsisted of aprepulse(whitenoiseat a low intensity stimulus, which elicits little or no 2, 4 or 8 dB SPL above the 70 dB SPL background), a Table 1 Sample size of each treatment group and experimental condition, and the sequence of behavioral testing Experiments Control PDTC Prenatal Poly(I:C) treatment(5 mg/kg) PDTC (100 mg/kg) Vehicle Prepulse inhibition 5♀7♂ 6♀5♂ 5♀5♂ 5♀5♂ Passive avoidance 6♀5♂ 5♀6♂ 6♀5♂ 4♀5♂ Active avoidance procedure 5♀5♂ 6♀5♂ 5♀5♂ 5♀6♂ Song et al. Behavioral and Brain Functions 2011, 7:50 Page 4 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 100 ms interval, and a startle pulse (40 ms, 120 dB SPL stimulus (US), an electric shock (0.3 mA) continuously white noise). The interval length between the 20 rando- applied to through the floor, associated with the presen- mized trials varied randomly from 8 to 23 s with an tation of a light (10 W), which served as a conditioned average of 15 s. stimulus (CS). The shuttle box had two compartments Startle responses were measured with the program (20 × 10 cm) connected by a 3 × 3 cm door. In the developed by Kunming Institute of Zoology, Chinese compartment containing the mouse, the CS was pre- Academy of Sciences, China. The peak value of the sented for 5 s followed by concurrent presentation of motor response between auditory stimuli onset and the CS and US for 25 s. At the end of the 30-s (total) 1,000 ms was automatically analyzed for each trial and period, the CS and the US were automatically turned the average response was calculated for each type of sti- off. A conditioned response was recorded when the ani- mulus. The amount of prepulse inhibition (PPI) was mal avoided the US by moving to the empty compart- expressed as the percentage decrease in the amplitude ment within 5 s of the onset of the CS. If animals failed of the startle response caused by presentation of the to avoid the shock, they could escape it by crossing dur- prepulse. The amplitude of the startle response without ing the US (25 s). Between each trial, there was an inter- a prepulse is p. When a weak stimulus is given prior to val of 30 s. The ratio of conditioned responses with the startle reflex stimulus, the amplitude for the startle respect to the total number of changes of compartment response is pp. The percentage of PPI for each rat was was also determined. calculated as (1-pp/p) × 100, which is proportional to The rats received 100 trials per day for 5 consecutive the inhibitory effect of PPI. Using this description of days [30]. Before the start of each session of trials, the PPI, a high degree of sensorimotor gating is reflected in rats were placed in the shuttle box for 10 min and a high % PPI value, whereas lower or no gating results allowed to explore. The final rate of active avoidance in a small or negative % PPI value. conditioned response was calculated as (total number of condition responses/500). Higher values indicated better Passive Avoidance Test learning and memory. The passive avoidance test is a fear-aggravated test used to assess short-term or long-term memory on small Data analysis laboratory animals. In this test, subjects learn to avoid Data analyses were conducted using SPSS 13.0 for Win- an environment in which an aversive stimulus (such as dows. Test results were presented as means ± standard a foot-shock) was previously delivered. The recent mem- deviations (SD). Cytokine data were analyzed using one- ory of the rats was tested in a passive avoidance-condi- way analysis of variance (ANOVA). Active avoidance tioning task. Two days after evaluation of general motor and passive avoidance test data were analyzed using activity, learning was evaluated in a single trial, passive repeated-measures ANOVA. PPI data were analyzed avoidance test. The conditioning and testing apparatus using multivariate analysis of variance (MANOVA) fol- consisted of a shuttle box (Ugo Basile model 7550, lowed by least significant difference (LSD) post hoc Comerio, Italy) equipped with a door to restrict access pair-wise comparisons for analysis of differences between illuminated and dark compartments of equal between groups. Bonferroni corrections were performed size. In the acquisition trial, a rat was placed in the illu- for multiple tests. minated compartment. After 30 s, the door separating the two compartments was opened. Some seconds later Results (T1), the animal spontaneously entered the dark com- Exposure of maternal rats to PolyI:C significantly partment. The door was shut 1 s after the crossing, and increased IL-10 and TNF-a protein levels in the mater- the rat was given a 0.5 mA, 3 s duration foot shock. nal serum (Table 2). Treatment effects were evident 3 h Twenty-four hours later (retention trial), the same pro- after exposure. Intervention with PDTC partially sup- cedure was repeated without a delay period to open the pressed the increase in cytokine levels. Rats treated only door and without an electric shock. The elapsed time to with PDTC showed no effects relative to control-treated enter the dark compartment was recorded as T2. rats. NF-B activation in maternal PBMC is not shown because it was below the detection limit. Active Avoidance Test To determine whether adult offspring from mothers The active avoidance task is a fear-motivated associative with different treatments have PPI defects, PP2, PP4, avoidance test based on electric current as a source of and PP8 were designated according to the decibel value punishment. This task provides a simple way to assess of prepulse startle stimuli (respectively 2, 4 or 8 dB SPL associative learning and memory of laboratory animals. above the 70 dB SPL background). As expected, the In a two-way shuttle box apparatus (Panlab, Barcelona), level of prepulse inhibition increased with increasing the rats were trained to avoid an aversive unconditioned prepulse intensity for all treatment groups. Multi-factor Song et al. Behavioral and Brain Functions 2011, 7:50 Page 5 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 Table 2 Serum Levels of IL-10 and TNF-a in animals Control group PDTC Group Model group Intervention group FP a, b a, b b IL-10(pg/mL) 0.19 ± 0.09 0.15 ± 0.09 19.14 ± 2.21 13.67 ± 0.97 632.049 < 0.001 a, b a, b b TNF-a(pg/mL) 11.96 ± 1.81 9.22 ± 3.00 128.48 ± 10.38 33.19 ± 2.91 983.570 < 0.001 a b One-way analysis of variance was used, P < 0.05. compared with model group, P < 0.05; compared with intervention group, P < 0.05. (treatment×prepulse intensities) ANOVA of %PPI group (P = 0.04). For the intervention group, this defect revealed a significant treatment effect (F = 58.867, P < was improved from the model group in both T1 (P = 0.001) (Figure 2). While the PDTC group did not differ 0.004) and T2 (P = 0.014). These results demonstrate from the control group, offspring from mothers injected improvements by PDTC treatment on memory impair- with PolyI:C exhibited significantly reduced %PPI relative ment in adult offspring from pregnant rats exposed to to controls (P < 0.05). The offspring from mothers trea- PolyI:C. ted with PolyI:C and PDTC had a higher %PPI (P < 0.05) Maternal exposure to PolyI:C significantly reduced the than the rats born to mothers treated with only PolyI:C. performance of adult offspring in an active avoidance Maternal exposure to PolyI:C significantly enhance PPI task (Figure 4). The offspring showed fewer conditioned defects of adult offspring, and this effect can be weakened responses compared to controls from the first training by treatment with PDTC after exposure. session. The performance deficit in offspring was PDTC treatment displays significant effect on the per- reduced by treatment of pregnant rats with PDTC after formance reduction of the adult offspring from maternal exposure to PolyI:C. Repeated measures ANOVA exposure to PolyI:C in a passive avoidance task (Figure revealed a significant main effect of day of training (F = 3). ANOVA showed a significant treatment effect (F = 434.264, P < 0.001), a significant effect of the treatment 135.010, P < 0.001). Offspring from the model group (F = 17.222, P < 0.001), and a significant interaction (mothers treated with only PolyI:C) had a longer T1 between these two factors (F = 6.934, P < 0.001). than offspring from the control group (P < 0.001), as Total conditioned response times were significantly different among offspring from the four treatment well as a shorter T2 than offspring from the control Control Group PDTC Group Model Group Intervention Group PP2 PP4 PP8 Figure 2 The effects of PDTC in prenatal PolyI:C administration on PPI of the adult offspring. PP2, PP4, and PP8 were designated according to the intensity of the prepulse (i.e., 2, 4 or 8 dB SPL above the 70 dB SPL background). Multivariate analysis of variance was used, LSD examination was used for Post hoc analysis, compared with control group, *P < 0.05; compared with intervention group, P < 0.05. Percent Prep ulse Inhibition Song et al. Behavioral and Brain Functions 2011, 7:50 Page 6 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 Control Group PDTC group Model Group Intervention Group T1 T2 Figure 3 The effects of PDTC in prenatal PolyI:C administration on passive avoidance behavior of the adult offspring. Acquisition (T1) and retention 24 h later (T2) were recorded. Multivariate analysis of variance was used, LSD examination was used for Post hoc analysis, compared with control group, *P < 0.05; compared with intervention group, P < 0.05. Control Group PDTC Group Model Group Intervention Group D1 D2 D3 D4 D5 Figure 4 The effects of PDTC in prenatal PolyI:C administration on active avoidance behavior of the adult offspring. The average number of conditioned changes in a shuttle box testing apparatus was recorded. Repeated measures ANOVA analysis of variance was used, compared among four groups, *P < 0.05. Number of Conditioned Changes Acquition(T1)/Retention 24h later(T2) Song et al. Behavioral and Brain Functions 2011, 7:50 Page 7 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 Table 3 Active avoidance of adult offspring ( x¯ ± s ) Control group PDTC Group Model group Intervention group ab ab Total reflex times 285.9 ± 42.36 279.36 ± 38.19 182.00 ± 21.97 205.00 ± 52.45 ab ab Total reflex rate 0.57 ± 0.085 0.56 ± 0.076 0.36 ± 0.043 0.41 ± 0.105 a b One-way analysis of variance was used, P < 0.05. compared with model group, P < 0.05; compared with intervention group, P < 0.05. groups (F = 17.22, P < 0.001; one-way ANOVA) (Table above indicated that PDTC, a kind of NF-B inhibitor, 3). The average reflex time was higher for the control can interfere with the inflammatory reactions mediated group than intervention and model groups (P <0.001 by cytokines. for both). No statistical difference was found between Behavioral deficits occurred in offspring from mother intervention group and model group. There were signifi- rats that had an immune response induced by PolyI:C cant differences in total response rates among offspring treatment. The offspring of the model group showed from thefourgroups; theratewas higher inoffspring weakened PPI and weakened latent inhibition. These from the control group compared to the intervention findings are consistent with Meyer [13], who reported and model groups (P = 0.002, P < 0.001). No statistical that administration of PolyI:C to pregnant mice led to a difference was found between the intervention group loss of PPI, loss of latent inhibition, and multiple schizo- and the model group. phrenia-like neuropathologic manifestations in the off- spring. Behavioral abnormalities were less severe in Discussion offspring from the intervention group compared to Both epidemiological and animal experimental studies offspring from the model group, demonstrating that have demonstrated that during early pregnancy, mater- inhibition of NF-B during pregnancy reduced neurode- nal immune response mediated by pro-inflammatory velopmental disorders in the offspring. cytokines is associated with higher risk for neuropsy- Latent inhibition exists in all classical and instrumen- chiatric disorders in the offspring [31,32]. It was tal conditioned reflexes, such as passive and active avoidance. Baruch et al. [37] first reported latent inhibi- reported that the NF-B inhibitor, which blocked the tion loss in schizophrenia patients, finding that acute NF-B signaling pathway and reduced cytokine release, was effective in many related diseases [33-35]. In this schizophrenic patients lost latent inhibition, while study, PolyI:C was administered to rats in early preg- chronic patients treated with antipsychotics presented nancy to stimulate the release of pro-inflammatory cyto- with normal latent inhibition. Several clinical studies kines. Maternal cytokine levels and the behavior of adult [38-40] further supported this result. Salgado [41] offspring were measured to explore the role of the cyto- reported that the dopamine antagonist amphetamine kine-mediated immune response during pregnancy in could cause loss of latent inhibition in normal healthy the development of psychiatric disorders. We also exam- people, and conversely, antipsychotics could enhance ined the effects of intervention with an NF-B inhibitor, latent inhibition. Similar results occurred in animals PDTC. [42]. In addition, individuals from schizophrenic parents In this study, serum levels of IL-10 and TNF-a in the showed abnormal latent inhibition. These studies model group (pregnant rats treated with PolyI:C) showed that abnormal latent inhibition in patients with increased significantly compared to levels in the control schizophrenia could be regarded as a stable manifesta- group. This imitated inflammatory reactions mediated tion and a cognitive deficit in behavior. In active avoid- by cytokines in maternal hosts after infection. Gayle et ance tests, the total conditioned reflex time in offspring al. [36] reported that PolyI:C, as well as LPS, could from the control group was significantly higher than in increase the cytokine level in the amniotic fluid and the the offspring from model group (PolyI:C-treated), imply- placenta of the maternal host. Increased cytokines could ing that latent inhibition abnormality, impaired learning, enter the circulatory system of the fetus. and impaired memory occurred in offspring from model group. In passive avoidance tests, the T1 and T2 in In our previous study, schizophrenic patients showed model group offspring were also significantly different activation of NF-B and elevated levels of cytokines from those in control group offspring, indicating that [27]. In the present study, activated NF-Bwas below the detection limit in our assays. In the intervention memory was impaired. These results are consistent with group, NF-B activation was inhibited through injection previous studies [13-15]. In the active avoidance test, a of PDTC and serum levels of IL-10 and TNF-a were significant effect of the treatment was found. However, suppressed relative to the model group. These results for total conditioned response times, the performance of provide indirect evidence that NF-B activation was suc- offspring from the intervention group and model group cessfully reduced in the intervention group. All the were not significantly different, demonstrating that NF- Song et al. Behavioral and Brain Functions 2011, 7:50 Page 8 of 9 http://www.behavioralandbrainfunctions.com/content/7/1/50 activation; NF-κB: Nuclear factor-kappa B; US: unconditioned stimulus; CS: B inhibition did not improve all behavioral outcomes conditioned stimulus; LSD: least significant difference; PBMC: peripheral in offspring from the intervention group. blood mononuclear cell; PPI: prepulse inhibition. The neurodevelopmental hypothesis of schizophrenia Acknowledgements posits a correlation between the disease and neurodeve- Funding for this study was provided by the National Natural Science lopmental disorders. It has been suggested that the Foundation of China (30971058 to X-QS; 81071090, 30870892 to L-XL), the maternal immune response to viral infections in preg- Natural Science Foundation of Henan (102300413208, 112300413226 to L- XL), the Program for Innovative Research Team (in Science and Technology) nancy may interfere with normal fetal brain develop- in University of Henan Province (2008IRTSTHN008 to L-XL); the Youth Fund ment. Motivated by this hypothesis, researchers have of the First Affiliated Hospital of Zhenzhou University (to X-QS). created many animal models to study the effects of pre- Author details natal and perinatal environments on schizophrenia. Department of Psychiatry, The First Affiliated Hospital of Zhengzhou Meyer [13] et al. reported that the PolyI:C treatment University, Zhengzhou, China. Department of Psychiatry, Henan Mental model in rats shared a wide range of characteristics with Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China. Henan Key Lab of Biological Psychiatry, Xinxiang Medical humans, and PolyI:C treatment effects manifested in University, Xinxiang, China. The Mental Health Institute of the Second post-pubescent offspring were consistent with the neural Xiangya Hospital, Central South University, Changsha, China. development hypothesis. We demonstrated that prenatal Authors’ contributions treatment with PolyI:C could elevate maternal cytokines LL and XS participated in the design of the study and made final approval and cause reduced PPI and reduced latent inhibition in of the version to be published. XS and WL were involved in drafting the adult offspring, confirming Meyer’s results. Current stu- manuscript and data analysis. CJ, YY and WL carried out the animal experiment JZ undertook revise the manuscript. 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Trigo JM, Cabrero-Castel A, Berrendero F, Maldonado R, Robledo P: MDMA Submit your next manuscript to BioMed Central modifies active avoidance learning and recall in mice. and take full advantage of: Psychopharmacology (Berl) 2008, 197(3):391-400. 31. Meyer U, Nyffeler M, Schwendener S, Knuesel I, Yee BK, Feldon J: Relative • Convenient online submission prenatal and postnatal maternal contributions to schizophrenia-related neurochemical dysfunction after in utero immune challenge. • Thorough peer review Neuropsychopharmacology 2008, 33(2):441-56. • No space constraints or color figure charges 32. Meyer U, Nyffeler M, Yee BK, Knuesel I, Feldon J: Adult brain and • Immediate publication on acceptance behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun • Inclusion in PubMed, CAS, Scopus and Google Scholar 2008, 22(4):469-86. • Research which is freely available for redistribution 33. 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