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/lp/springer-journals/age-related-changes-in-neuroinflammation-and-prepulse-inhibition-in-TyNXqItePA
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- Springer Journals
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- Copyright © 2019 by The Author(s)
- Subject
- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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- 1744-9081
- DOI
- 10.1186/s12993-019-0154-2
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Abstract
Background: Maternal immune activation (MIA) during gestation can increase the later risk of schizophrenia in adult offspring. Neuroinflammation is believed to underlie this process. Postmortem brain studies have found changes in the neuroimmune systems of patients with schizophrenia. However, little is known about the dynamic changes in cerebral inflammation and behavior during the course of the disease. Methods: Here, the prepulse inhibition (PPI) test was conducted in adolescent and adult Sprague–Dawley rats prenatally challenged with polyriboinosinic–polyribocytidylic acid (Poly I:C) on gestational day 9 to determine the behavioral trajectory triggered by early exposure to Poly I:C. Brain immune changes were determined in the prefrontal cortex (PFC) and hippocampus (HC) at both ages. The status of the microglia and astrocytes was determined with immunohistochemical staining. The levels of IL-6, IL-1β, and TNF-α in both brain regions were evaluated with enzyme- linked immunosorbent assays. Results: Disrupted PPI, the core phenotype of schizophrenia, only emerged in adulthood. Behavioral changes dur- ing puberty and adulthood were both accompanied by the activation of microglia (PFC and HC). Astrocytes were only activated at PN60. The levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the offspring of the Poly I:C-exposed mothers differed with brain region and time, with more cytokines elevated during periadolescence than during adulthood. Conclusions: Our findings indicate that immune activation emerged before symptom manifestation in the offspring of MIA rats. We conclude that early prenatal Poly I:C challenge can lead to age-related behavioral and neuroinflam- matory changes. These data provide new insight into the neuroinflammatory and neuropathological mechanisms underlying the development of schizophrenia. They also suggest that periadolescence could be more important than adulthood in the prevention and treatment of schizophrenia. Keywords: Maternal immune activation, Schizophrenia, Poly I:C, Microglia, Astrocyte pathogenesis of schizophrenia involves an interplay Background between genetic and environmental factors. Although Schizophrenia is a chronic and devastating disor- the genetic contribution is large [2], the importance of der affecting ~ 1% of the world population [1]. The the environment in the development of this disease is increasingly recognized. *Correspondence: lwq781603@163.com; lvx928@126.com † Epidemiological surveys have indicated that prena- Shuang Ding and Yunqing Hu contributed equally to this work as first authors tal maternal infections with various infectious agents Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang are risk factors for the development of schizophrenia in Medical University, No. 388, Jianshe Middle Road, Xinxiang 453002, the adult offspring [3–6]. Examples include influenza Henan, People’s Republic of China Full list of author information is available at the end of the article virus, rubella, cytomegalovirus, Herpes simplex virus 2, © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ding et al. Behav Brain Funct (2019) 15:3 Page 2 of 10 Chlamydia, Toxoplasma gondii, and Borna disease virus. schizophrenia-like behaviors and neuroimmunologi- Interestingly, diverse inflammatory events can have simi - cal abnormalities. Among these are defects in the pre- lar consequences on the brain. Therefore, it has been pos - pulse inhibition (PPI) and cognition [34], impairment of tulated that the effects on behavior and brain function locomotor activities, deficits in learning skills, the dys - may depend on the immune responses and factors that regulation of neurotransmission [7, 35], and brain mor- mediate these processes, such as cytokines and immune phological abnormalities [36, 37]. Therefore, the Poly I:C cells, rather than specific pathogens. Researches in ani - MIA model has become a powerful tool in the investi- mal models of maternal immune activation (MIA) sug- gation of the progressive nature of schizophrenia. This gest that synthetic viruses or bacterial analogues can model has also been used to develop therapeutic and also lead to behavioral changes related to schizophrenia, preventive strategies to halt disease progression [38], further supporting the notion that inflammation is a key which indirectly indicate possible mechanisms underly- player in the pathophysiology of this disorder [7]. ing disease. In one study, Osborne et al. have shown that Today, there is renewed interest in brain inflam - CBD, a component with anti-inflammatory property, matory changes and the key roles they play in the can attenuate cognitive deficits and the social interac - pathophysiological mechanisms of schizophrenia [8]. tion induced by prenatal Poly I:C infection [34]. Another Emerging evidence indicates that neuroinflammation experimental research using Poly I:C MIA model has is related to schizophrenia [9–11]. For instance, the suggested that minocycline treatment can prevent the expression of immune-related genes is increased in the behavioral aberrations and microglial changes associ- prefrontal cortices of schizophrenic patients [12], and ated with schizophrenia [39]. Besides, the administration there is also evidence that cytokine levels are abnor- of cyclo-oxygenase 2 inhibitors, an anti-inflammatory mal in the cerebrospinal fluid and specific brain areas medication, in the early stages of schizophrenia has had of patients with schizophrenia [13–16]. The immune beneficial effects [40]. Taken together, these studies sug - processes of the central nervous system (CNS) are gest the potential utility of treating inflammation in the complex and are still only partly understood. Micro- asymptomatic period of schizophrenia to prevent disease glia and astrocytes are the major immune cells in the development. brain [17, 18], and postmortem studies have shown For a long time, the mid-late prenatal period was increased cerebral microgliosis and astrogliosis in thought to be the only risk window in which schizophre- schizophrenic patients [19–23], although not consist- nia developed based on the initial human epidemiologi- ently [24–27]. In fact, microglia are the main resident cal studies [6], and many researchers have examined this immune cell population in the CNS. When the environ- with the rodent equivalent, gestational day (GD)15 or ment changes, microglia are usually the first to alter in GD17 as the date for Poly I:C stimulation [34–36]. How- morphology and function to react to those challenges ever, several studies have reported that early prenatal [28], and their activation is believed to be linked to the insult also results in psychiatric diseases [41], an impor- pathophysiology of schizophrenia [29]. Like microglia, tant but long-ignored fact. Several experimental studies astrocytes also have immunological functions, although pinpointed the precise stage of pregnancy at which infec- less importance has been ascribed to them as to those tion may cause different behavioral phenotypes [42]. MIA of microglia. Astrocytes, the largest and most numer- at GD9 specifically induces abnormal behaviors, which ous glial cells in the CNS, also produce pro- and anti- are related to the positive symptoms of schizophrenia, inflammatory cytokines, including interleukin (IL)-1, while Poly I:C exposure on GD17 could cause mostly IL-6, tumor necrosis factor α (TNF-α), transforming negative symptoms [43]. However, there are limited data growth factor β (TGF-β), interferon (IFN)-α, and IFN- regarding the abnormalities in rat after early prenatal β, that participate in the innate and adaptive immune MIA, especially alternations of astrocyte as mentioned processes in the brain [30, 31]. Although many stud- above. ies have confirmed the involvement of microglia in Therefore, we tested the hypothesis that MIA induced schizophrenia, the role of astrocytes remains very by exposure to Poly I:C at GD9 induces age-related controversial. behavioral and neuroinflammatory changes in the To better understand the pathogenic mechanism of offspring. schizophrenia, animal models of MIA have been estab- lished [32, 33]. Polyriboinosinic–polyribocytidylic acid Methods (poly[I:C]), a synthetic double-stranded RNA, mim- Animals ics viral infection by activating toll-like receptor 3 [32]. Eight-week-old male and female Sprague–Dawley rats Numerous studies have shown that the offspring of were obtained from a specific-pathogen-free breeding pregnant dams treated with Poly I:C show a battery of colony at the Experimental Animal Center of Zhengzhou Ding et al. Behav Brain Funct (2019) 15:3 Page 3 of 10 University (Zhengzhou, China). The animals came from prepulse (75, 80, or 85 dB) alone, and no stimulus. Test- multiple litters. Littermates of the same sex were caged ing was completed within 40 min. The results, designated together, with 3–4 per cage. Breeding began after 2 weeks PP75, PP80, and PP85, were calculated automatically of acclimation to the new animal holding room. The pro - by the system software. The percentage PPI induced by cedures for breeding and for the verification of pregnancy each prepulse intensity was calculated as [1 − (startle have been described by Meyer [44]. The rats were housed amplitude on prepulse trial/startle amplitude on pulse individually in ventilated plastic cages at 22 ± 2 °C and alone)] × 100% [46]. 50 ± 10% relative humidity with a constant day–night cycle (light: 08:00–20:00 h). Food and tap water were available ad libitum. The Animal Care and Use Commit - Immunohistochemical (IHC) study tee of the Henan Key Laboratory of Biological Psychiatry We chose 23 animals (13 males as cases; 10 males as (Xinxiang, China) approved the use of the rats and the controls) at PN60 and 23 animals (15 males as cases; 8 experimental protocols in this study. males as controls) at PN40 for the IHC study to observe the morphological changes in the activated microglia MIA during pregnancy and astrocytes in the prefrontal cortex (PFC) and hip- The timed pregnant mice were injected intravenously pocampus (HC) of the offspring brains. The animals were with 0.1 mL of saline or 10 mg/kg Poly I:C (Sigma- anesthetized with isoflurane and perfused with 4% para - Aldrich, St. Louis, State of Missouri, USA) on GD9. All formaldehyde. They were postfixed overnight and cry - the animals were immediately returned to their home protected in 30% sucrose solution for 48 h at 4 °C. Serial cages after injection. On postnatal day (PN) 21, both sections of the brain were cut to 20 μm with a cryostat groups of pups were weaned, then housed 3–4 to a cage microtome (Leica CM1850). Six discontinuous slices according to sex and litter. Half of each group was main- of each region of each brain were selected to count the tained undisturbed until 6 weeks of age (PN40), and the densities of microglia and astrocytes under an optical rest until 8 weeks of age (PN60), which correspond to microscope. The slices were rinsed in PBS, and stored periadolescence and young adulthood, respectively, in at − 20 °C until further processing. For immunostain- humans [45]. ing, the slices were rinsed three times for 10 min in PBS. Blocking was done in 5% normal serum for 1 h at room temperature. The following primary antibodies were Behavioral testing used: goat anti-IBA1 primary antibody (1:500; Abcam, A total of 20 animals (11 males for cases; 9 males for con- Cambridge, UK), rabbit anti-GFAP (1:300, Boster, Wu trols) and 21 animals (13 males for cases; 8 males for con- Han, China). They were incubated overnight at room trols) were randomly selected at PN40 (adolescent stage) temperature. After three washes with PBS (2 min each), and PN60 (young adult stage), respectively, for behavioral the sections were incubated for 1 h with the biotinylated tests to evaluate the manifestations of schizophrenia-like secondary antibodies diluted 1:500. Sections were behavior. All behavioral tests were performed between washed again three times for 2 min in PBS and incu- 08:00 and 18:00 h. bated with the strept avidin–biotin complex for 1 h. Then rinsed again four times for 5 min in PBS, dehydrated, and PPI test coverslipped with Eukitt (Kindler, Freiburg, Germany). PPI was tested in four sound-attenuated chambers. All The GFAP-labeled slices were counterstained with 0.25% test sessions were performed in a single-chamber startle cresyl violet according to standard protocols. After stain- apparatus (QMC-I, Kunming Institute of Zoology, Chi- ing, the sections were dehydrated through an alcohol nese Academy of Sciences, China). After the mice were series, cleared with xylene, and coverslipped with Eukitt. allowed to adapt for 5 min, the white noise was set to 70 decibels (dB) for 10 pretests, and then rats went to the Enzyme‑linked immunosorbent assays (ELISAs) test phase, as previously described [46]. The experiment Three pregnant rats were humanely killed about 3 h after consisted of 40 rounds of stimulation, which began with the administration of Poly I:C or vehicle at G9. And we a delay of ~ 50 ms, followed by a 20 ms pulse stimulation respectively chose 15 animals (8 males as cases; 7 males with white noise (75, 80, or 85 dB), followed by a 100 ms as controls) at PN60 and at PN40 for the ELISA study delay, and then a 40 ms stimulation of the startle reflex to observe the expression level changes in the prefron- with white noise of 120 dB. The last was 290 ms to record tal cortex (PFC) and hippocampus (HC) of the offspring time. Each trial was completed in 500 ms, and the aver- brains. The plasma from their heart blood was isolated age mutation interval was 15 s. In this experiment, eight within 30 min of collection by centrifugation for 20 min different types of stimuli were supplied: pulse stimula - at 1000×g, and the samples were then stored as aliquots tion, prepulse (75, 80, or 85 dB) + pulse stimulation, Ding et al. Behav Brain Funct (2019) 15:3 Page 4 of 10 at ≤ − 70 °C before their IL-1β, IL-6, and TNF-α concen- trations were measured. Some offspring of the animals in each group were humanely killed at both ages, and tissue homogenates (diluted 1:10 in 0.9% saline) of the target brain regions were separated to measure the concentra- tions of IL-1β, IL-6, and TNF-α. The subsequent proce - dures were all performed with highly sensitive ELISAs from R&D Systems (Minneapolis, Minnesota, USA), according to the manufacturer’s instructions. Statistical analyses The data are presented as means ± standard deviations and were analyzed with SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Student’s t test was used for the data analysis, according to the nature of the data. All results are two- sided, and the level of significance is α = 0.05. Results PPI test Figure 1 shows the effects of early prenatal Poly I:C admin - istration on PPI deficits in the adolescent and adult rat off - spring. The adult offspring displayed significant inhibition Fig. 1 Eec ff ts of early maternal immune activation on prepulse inhibition in rat offspring. Data are shown as mean ± SEM. N = 10 for (all P < 0.01) compared with the control offspring in all the each group. a Maternal immune activation produced no significant dB groups (72, 74, and 78 dB), whereas the adolescent off - differences in any dB group (70, 75, or 80 dB) in adolescence. b spring did not. These results confirm that MIA in the first Prepulse inhibition defects were observed in all dB groups (70, trimester can induce disrupted PPI after puberty in rats, 75, and 80 dB) in adult offspring of dams exposed to Poly I:C at which is similar to the findings in schizophrenia patients. gestational day 9. ***P < 0.001 Analysis of microglial markers the astrocytes did not differ significantly between the In both the PFC and HC, more activated microglia were two groups on PN40, but on PN60, the optical density of observed in the Poly I:C offspring at the age of either glial fibrillary acidic protein-positive astrocytes in these 40 or 60 days than in the corresponding controls. Fig- brain regions of the MIA rat offspring was significantly ure 2 clearly suggests increased numbers of microglia higher when compared with control group (all P < 0.001). in both the regions examined in the Poly I:C-treated Besides, the hypertrophic astrocyte morphology had offspring. The morphology of the microglia in the two increased in the MIA rat offspring. target regions also clearly differs from that in the vehicle- treated offspring. In detail, the activated microglia in the Analysis of proinflammatory cytokines offspring of the MIA rats were characterized by enlarged As shown in Fig. 6, expression of all three cytokines cell bodies, with retracted and thickened processes, (IL-1β, IL-6 and TNF-α) have elevated in pregnant rats which differed from the microglia in the quiescent state administrated with Poly I:C, which have validated our suc- observed in vehicle-treated offspring, which had round cessful injection. Additionally, proinflammatory cytokine cell bodies and thin processes, with simple ramifications. levels changed differently in the two groups of rat off - We counted number of Iba1-immunopositive cells in spring at different stages, as shown in Fig. 7. The Poly I:C- the PFC and HC for statistical comparison. As shown in treated pubescent offspring showed significantly higher Fig. 3a, b, two-sided Student’s t test analysis revealed that concentrations of IL-1β and IL-6 than the controls in both the number of Iba1-immunopositive cells in these brain the PFC and HC. In the young adult offspring, no signifi - regions of Poly I:C-treated group was significantly higher cant differences were detected in the HC, whereas in the when compared with control group (all P < 0.001). PFC, the levels of TNF-α and IL-6 were elevated. The Poly I:C treatment did not affect the concentrations of TNF-α Analysis of astrocyte markers in the HC in either the pubescent or young adult rats. Figure 4 shows the age-dependent status of the astrocytes in the prenatally Poly I:C-treated rats. As shown in Fig. 5, Ding et al. Behav Brain Funct (2019) 15:3 Page 5 of 10 Fig. 2 Eec ff ts of early maternal immune activation on microglial activation in the prefrontal cortex (PFC) and hippocampus (HC) regions of offspring. A–D Representative images of immunohistochemical staining for ionized calcium-binding adapter molecule 1 (IBA1) in PFC of rats after early prenatal treatment with Poly I:C (A, C) or vehicle (B, D). Row 1 and row 2: During puberty (row 1) and adulthood (row 2), IBA1-positive cells in the PFC were with round cell bodies and reduced arborizationin the offspring of rats exposed to Poly I:C at gestational day 9; n = 9 for Poly I:C group, n = 7 for vehicle group. E–H Representative images of immunohistochemical staining for IBA1 in HC of rats after early prenatal treatment with Poly I:C (E–G) or vehicle (F–H); n = 13 for Poly I:C group, n = 10 for vehicle group. Row 3 and row 4: IBA1-positive cells in the HC were also with round cell bodies and reduced arborization during puberty (row 3) and adulthood (row 4) in the offspring of rats exposed to Poly I:C at GD9 (×10) Fig. 3 Comparison of number of ionized calcium-binding adapter molecule 1 (IBA1)-immunopositive cells in prefrontal cortex (a), hippocampus (b) between pubescent and adult offspring based on Student’s t test. The data is shown as mean ± SEM. *P < 0.05, ***P < 0.001 functional profiles of microglia, astrocytes, and cytokines with regard to the progressive behavioral changes that Discussion occurred from puberty to young adulthood in a Poly I:C- Schizophrenia typically emerges in late adolescence or induced rat model of MIA. early adulthood. Studies in adulthood can help us under- Sensorimotor gating is one of the core biological fea- stand the characteristics of this disease, whereas research tures of schizophrenia [47]. Auditory sensory gating can that focuses on adolescence may provide targets for be detected with the PPI test in both patients and animal preventive strategies. In this study, we investigated the ▸ Ding et al. Behav Brain Funct (2019) 15:3 Page 6 of 10 Fig. 4 Eec ff ts of early maternal immune activation on astrocytes in the prefrontal cortex and hippocampus regions of offspring. A–D Representative images of immunohistochemical staining for glial fibrillary acidic protein (GFAP) in the PFC of rats after early prenatal treatment with Poly I:C (A, C) or vehicle (B, D); n = 15 for Poly I:C group; n = 8 for vehicle group. During puberty (row 1, row 3), there were no significant differences in astrocytes in the two target brain regions. E–H Representative images of immunohistochemical staining for GFAP in the HC of rats after early prenatal treatment with Poly I:C or vehicle; n = 9 for Poly I:C group; n = 7 for vehicle group. Row 2 and row 4: during adulthood, GFAP-positive cells with a hypertrophic morphology were observed in the PFC and HC of offspring of mice exposed to Poly I:C at gestational day 9 (×10) pregnancy enhances the risk of schizophrenia in the adult offspring [46]. Therefore, many preclinical animal stud - ies have been performed to confirm this finding. Several studies then demonstrated that immune stimulation dur- ing early gestation may also be critical [41]. However, preclinical information is limited, especially in rats. Our data provide new evidence of this phenomenon. We found that all three components involved in the neural immune process (microglia, astrocytes, and cytokines) were altered in the Poly I:C-treated offspring during development and that these changes displayed distinct patterns. Our results suggest that at PN40, the microglia were already activated, and this activation persisted into early adulthood. This is consistent with a previous study in the neonatal offspring of Poly I:C-chal - lenged rats [49]. However, two published studies of mice reported that microglia were only activated at PN30, not PN100 [48, 50], and Zhu et al. noted that the numbers of IBA1-positive microglia in the HC and cerebral cor- tex were increased in the adult (PN 62) offspring of Poly I:C-treated rats [51]. A possible interpretation of these discrepancies is that microglial activation varies with the animal strain, the time of stimulation, the brain region tested, and the age of the offspring examined. There - fore, as the major immune cell population in the brain, microglia are believed to participate in the pathogenesis of schizophrenia, although the time of their activation remains controversial. Consistent with the behavioral findings, astrocytes were only activated in early adulthood in the MIA rat off - spring, which may indicate a crucial link between behav- ioral abnormalities and astrocyte activation. Although studies have reported no significant changes in the astro - models. Our data confirm that the administration of cytes of patients with schizophrenia [27], the samples Poly I:C in the first trimester causes PPI defects in early examined were usually highly heterogeneous, with vari- adulthood. This result is consistent with other research ous confounding factors, such as antipsychotic medica- with Poly I:C-induced animal models of infection dur- tion and illness stage. In our experiment, we documented ing pregnancy and the clinical characteristics of schizo- astrogliosis in the young adult offspring of MIA rats and phrenia [48]. The initial epidemiological data suggested compared it with that in the controls. A recent study that maternal viral challenge during mid or late human detected reactive astrocytes in subsets of people with ▸ Ding et al. Behav Brain Funct (2019) 15:3 Page 7 of 10 Fig. 5 Comparison of optical density of glial fibrillary acidic protein (GFAP)-immunopositive cells in prefrontal cortex (a), hippocampus (b) between pubescent and adult offspring based on Student’s t test. The data is shown as mean ± SEM. *P < 0.05 schizophrenia with high levels of inflammatory markers in the PFC [52]. Therefore, we speculate that inflamma - tion may be a link between astrocytes and PPI, and this warrants further investigation. It is noteworthy that the offspring of rats with early maternal MIA displayed more-elevated cytokines in ado- lescence than in adulthood. As well as being age-related, these cytokine changes were also region-specific. In PFC, Fig. 6 Cytokine (IL-1β, IL-6, and TNF-α) Levels of pregnant rats treated with Poly I:C or NaCl on gestational day 9. All of these the majority of cytokines were elevated in adolescence, cytokines elevated in the blood of Poly I:C rats. Data are shown as and only elevated IL-6 persisted into adulthood. No mean ± SEM; n = 3 for each group. a Concentrations (pg/mg) of IL-1β; changes in TNF-α levels were observed until adulthood. b concentrations (pg/mg) of IL-6; c concentrations (pg/mg) of TNF-α. The changes in the HC differed from those in the PFC, *P < 0.05 and the levels of most cytokines (including IL-6) were only increased during puberty, and not in adulthood. Notably, IL-6 is an important cytokine in cerebral func- based on the facts that neuroinflammation and cytokines tion [53, 54] and is associated with schizophrenia [55]. are altered in the brains and cerebrospinal fluid of schizo - Smith and his colleagues found that the adult offspring phrenia patients [57, 58]. At the same time, it posed an of mice prenatally administered IL-6 displayed schizo- interesting question as to how cytokine cause schizo- phrenia-like deficits, and that the coadministration of phrenia. One study shown that cytokine proteins inhibit an anti-IL-6 antibody to the mouse model prevented the hippocampal neurogenesis and the level of microglia was aberrant phenotype [56]. negatively correlated with neurogenesis [59]. Besides, It has been suggested that the injection of Poly I:C into neuroinflammation may influence the glutamatergic and pregnant rats alters the brain cytokines of their offspring, dopamine system [60, 61]. Ding et al. Behav Brain Funct (2019) 15:3 Page 8 of 10 Fig. 7 Eec ff ts of early maternal immune activation (MIA) on cytokines (IL-1β, IL-6, and TNF-α) in the prefrontal cortex (PFC) and hippocampus (HC) regions of MIA rat offspring during adolescence and adulthood. Overall, most of these cytokines behaved in region- and age-related manners. Data are shown as mean ± SEM; n = 8 for Poly I:C group, n = 7 for vehicle group. a–c Concentrations (pg/mg) of IL-1β, IL-6, and TNF-α in the PFC during adolescence and adulthood. d–f Concentrations (pg/mg) of IL-1β, IL-6, and TNF-α in the HC during adolescence and adulthood. *P < 0.05 Clinical data predict that inflammatory cytokines Conclusion increase progressively in the brains of MIA offspring, but In summary, early maternal infection can induce there is little detailed information on the changes at dif- immune activation, causing increases in activated ferent stages of development, especially in adolescence. A gliosis and proinflammatory cytokines in the off- recent study by has provided some evidence for this, and spring at two key ages, especially periadolescence. our data are consistent with it [14]. However, previous This may be a more important stage than young adult- studies have lacked the corresponding behavioral infor- hood for the pathogenesis of schizophrenia, leading to mation. More importantly, our findings may be the first abnormal behavior in the adult stage. From this per- to relate the status of astrocytes and PPI. spective, interventions that regulate immunological While our study has explored two key time points of activity in an early developmental stage may be impor- schizophrenia, it still has some limitation. First, we doc- tant and offer promising therapeutic strategies for umented that evident neuroinflammation has already schizophrenia. existed at adolescence, but what is the situation with earlier developmental stages? In the future, we will pro- Abbreviations vide more information about neuro-immune process MIA: maternal immune activation; PPI: prepulse inhibition; PN: postnatal day; from fetal to late adult brains in animal models. Second, Poly I: C: polyriboinosinic–polyribocytidylic acid; PFC: prefrontal cortex; HC: hippocampus; Iba1: ionized calcium-binding adapter molecule 1; GFAP: glial we found the same turning point of both astrocyte and fibrillary acidic protein; CNS: central nervous system; IL: interleukin; TNF-α: PPI, which needs further precise investigation in if spe- tumor necrosis factor α; TGF-β: transforming growth factor β; IFN: interferon; cific status of astrocyte contribute to specific behavioral GD: gestational day; IHC: immunohistochemical. abnormalities in offspring. Ding et al. Behav Brain Funct (2019) 15:3 Page 9 of 10 Authors’ contributions 6. Mednick SA, et al. Adult schizophrenia following prenatal exposure to an LXL and WQL designed the study, wrote the protocol and prepared the manu- influenza epidemic. Arch Gen Psychiatry. 1998;45:189–92. script. SD and YQH established the animal model of early maternal immune 7. Winter C, et al. Prenatal immune activation leads to multiple changes activation and undertook the statistical analysis. BBL, YQC, KKH helped in in basal neurotransmitter levels in the adult brain: implications for brain interpretation of the study. YFY, YZ, XJW helped with sample preparation and disorders of neurodevelopmental origin such as schizophrenia. Int J molecular biology techniques. MLD, HXZ ascertained the samples. All authors Neuropsychopharmacol. 2009;12:513–24. read and approved the final manuscript. 8. Kirkpatrick B, Miller BJ. Inflammation and schizophrenia. Schizophrenia Bull. 2013;39:1174. Author details 9. Trepanier MO, et al. Postmortem evidence of cerebral inflammation in Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical schizophrenia: a systematic review. Mol Psychiatry. 2016;21:1009. University, No. 388, Jianshe Middle Road, Xinxiang 453002, Henan, People’s 10. Kahn RS, Sommer IE. The neurobiology and treatment of first-episode Republic of China. Henan Key Lab of Biological Psychiatry of Xinxiang schizophrenia. Mol Psychiatry. 2015;20:84–97. Medical University, Xinxiang, China. International Joint Research Laboratory 11. Van Kesteren CFMG, et al. Immune involvement in the pathogenesis for Psychiatry and Neuroscience of Henan, Xinxiang, China. of schizophrenia: a meta-analysis on postmortem brain studies. Transl Psychiatry. 2017;7:e1075. Acknowledgements 12. Arion D, et al. Molecular evidence for increased expression of genes We thanked Professor Dai Zhang who gave us instructive suggestions during related to immune and chaperone function in the prefrontal cortex in the conduction of our research. We also thanked International Science Editing. schizophrenia. Biol Psychiatry. 2007;62:711. (http://www.inter natio nalsc ience editi ng.com) for editing this manuscript. 13. Monji A, et al. Neuroinflammation in schizophrenia especially focused on the role of microglia. Progress Neuro Psychopharmacol Biol Psychiatry. Competing interests 2013;42:115. The authors declare that they have no competing interests. 14. Garay PA, et al. Maternal immune activation causes age- and region-spe- cific changes in brain cytokines in offspring throughout development. Availability of data and materials Brain Behav Immunity. 2013;31:54. The datasets used and/or analyzed during the current study are available from 15. Miller BJ, et al. Prenatal inflammation and neurodevelopment in schizo - the corresponding authors upon reasonable request. phrenia: a review of human studies. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:92–100. Consent for publication 16. Söderlund J, et al. Activation of brain interleukin-1beta in schizophrenia. Not applicable. Mol Psychiatry. 2009;14:1069–71. 17. Takahashi N, Sakurai T. Roles of glial cells in schizophrenia: possible Ethics approval and consent to participate targets for therapeutic approaches. Neurobiol Dis. 2013;53:49. All experimental protocols and procedures were approved by the Animal Care 18. Schwarz JM, Bilbo SD. Sex, glia, and development: interactions in health and Use Committee of the Henan Key Lab of Biological Psychiatry (Xinxiang, and disease. Horm Behav. 2012;62:243–53. China). 19. Bayer TA, et al. Evidence for activation of microglia in patients with psy- chiatric illnesses. Neurosci Lett. 1999;271:126–8. Funding 20. Fillman SG, et al. Increased inflammatory markers identified in the dorso - The work was supported by the National Natural Science Foundation of China lateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry. (Grand Nos. 81671330, U1704190), Training plan for young excellent teachers 2013;18:206–14. in Colleges and Universities of Henan (No. 2016GGJS-106), High Scientific 21. Radewicz K, et al. Increase in HLA-DR immunoreactive microglia in frontal and Technological Research Fund of Xinxiang Medical University (Grand Nos. and temporal cortex of chronic schizophrenics. J Neuropathol Exp Neu- 2017ZDCG-04), National Key Research and Development Program of China rol. 2000;59:137–50. (Grand Nos. 2016YFC1307001, 2016YFC0904301), Medical science and tech- 22. Barley K, Dracheva S, Byne W. Subcortical oligodendrocyte- and astro- nology research project of Henan Province (Grand Nos. 201702131), The sci- cyte-associated gene expression in subjects with schizophrenia, major ence and technology project of Henan Province (192102310086), Innovation depression and bipolar disorder. Schizophrenia Res. 2009;112:54–64. Scientists and Technicians Troop Construction Projects of Henan Province (No. 23. Feresten AH, et al. Increased expression of glial fibrillary acidic protein in 174100510024), the support project for the Disciplinary group of Psychiatry prefrontal cortex in psychotic illness. 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Behavioral and Brain Functions – Springer Journals
Published: Mar 5, 2019