Maternal immune activation alters nonspatial information processing in the hippocampus of the adult offspring

The observation that maternal infection increases the risk for schizophrenia in the offspring suggests that the maternal immune system plays a key role in the etiology of schizophrenia. In a mouse model, maternal immune activation (MIA) by injection of poly(I:C) yields adult offspring that display abnormalities in a variety of behaviors relevant to schizophrenia. As abnormalities in the hippocampus are a consistent observation in schizophrenia patients, we examined synaptic properties in hippocampal slices prepared from the offspring of poly(I:C)- and saline-treated mothers. Compared to controls, CA1 pyramidal neurons from adult offspring of MIA mothers display reduced frequency and increased amplitude of miniature excitatory postsynaptic currents. In addition, the specific component of the temporoammonic pathway that mediates object-related information displays increased sensitivity to dopamine. To assess hippocampal network function in vivo, we used expression of the immediate-early gene, c-Fos, as a surrogate measure of neuronal activity. Compared to controls, the offspring of poly(I:C)-treated mothers display a distinct c-Fos expression pattern in area CA1 following novel object, but not novel location, exposure. Thus, the offspring of MIA mothers may have an abnormality in modality-specific information processing. Indeed, the MIA offspring display enhanced discrimination in a novel object recognition, but not in an object location, task. Thus, analysis of object and spatial information processing at both synaptic and behavioral levels reveals a largely selective abnormality in object information processing in this mouse model. Our results suggest that altered processing of object-related information may be part of the pathogenesis of schizophrenia-like cognitive behaviors.     

Increased affective ultrasonic communication during fear learning in adult male rats exposed to maternal immune activation

Maternal exposure to infection during pregnancy greatly increases the risk of psychopathology in the offspring. In support of clinical findings, rodent models of maternal immune activation (MIA) show that prenatal exposure to pathogens can induce phenotypic changes in the offspring associated with schizophrenia, autism, depression and anxiety. In the current study, we investigated the effects of MIA via polyinosinic:polycytidylic acid (poly I:C) on emotional behavior and communication in rats. Pregnant rats were administered poly I:C or saline on gestation day 15 and male offspring were tested in an auditory fear conditioning paradigm in early adulthood. We found that prenatal poly I:C exposure significantly altered affective signaling, namely, the production of aversive 22-kHz ultrasonic vocalizations (USVs), in terms of call number, structure and temporal patterning. MIA led to an increase in aversive 22-kHz USVs to 300% of saline controls. Offspring exposed to MIA not only emitted more 22-kHz USVs, but also emitted calls that were shorter in duration and occurred in bouts containing more calls. The production of appetitive 50-kHz USVs and audible calls was not affected. Intriguingly, alterations in aversive 22-kHz USV emission were observed despite no obvious changes in overt defensive behavior, which highlights the importance of assessing USVs as an additional measure of fear. Aversive 22-kHz USVs are a prominent part of the rat's defensive behavioral repertoire and serve important communicative functions, most notably as alarm calls. The observed changes in aversive 22-kHz USVs show that MIA has long-term effects on emotional behavior and communication in exposed rat offspring.     

Risperidone Administered During Asymptomatic Period of Adolescence Prevents the Emergence of Brain Structural Pathology and Behavioral Abnormalities in an Animal Model of Schizophrenia

Schizophrenia is a disorder of a neurodevelopmental origin manifested symptomatically after puberty. Structural neuroimaging studies show that neuroanatomical aberrations precede onset of symptoms, raising a question of whether schizophrenia can be prevented. Early treatment with atypical antipsychotics may reduce the risk of transition to psychosis, but it remains unknown whether neuroanatomical abnormalities can be prevented. We have recently shown, using in vivo structural magnetic resonance imaging, that treatment with the atypical antipsychotic clozapine during an asymptomatic period of adolescence prevents the emergence of schizophrenia-like brain structural abnormalities in adult rats exposed to prenatal immune challenge, in parallel to preventing behavioral abnormalities. Here we assessed the preventive efficacy of the atypical antipsychotic risperidone (RIS). Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) or saline. Their male offspring received daily RIS (0.045 or 1.2 mg/kg) or vehicle injection in peri-adolescence (postnatal days [PND] 34–47). Structural brain changes and behavior were assessed at adulthood (from PND 90). Adult offspring of poly I:C–treated dams exhibited hallmark structural abnormalities associated with schizophrenia, enlarged lateral ventricles and smaller hippocampus. Both of these abnormalities were absent in the offspring of poly I:C dams that received RIS at peri-adolescence. This was paralleled by prevention of schizophrenia-like behavioral abnormalities, attentional deficit, and hypersensitivity to amphetamine in these offspring. We conclude that pharmacological intervention during peri-adolescence can prevent the emergence of behavioral abnormalities and brain structural pathology resulting from in utero insult. Furthermore, highly selective 5HT_2A receptor antagonists may be promising targets for psychosis prevention.     

Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders

Both genetic and environmental factors are thought to contribute to neurodevelopmental and neuropsychiatric disorders with maternal immune activation (MIA) being a risk factor for both autism spectrum disorders and schizophrenia. Although MIA mouse offspring exhibit behavioral impairments, the synaptic alterations in vivo that mediate these behaviors are not known. Here we employed in vivo multiphoton imaging to determine that in the cortex of young MIA offspring there is a reduction in number and turnover rates of dendritic spines, sites of majority of excitatory synaptic inputs. Significantly, spine impairments persisted into adulthood and correlated with increased repetitive behavior, an ASD relevant behavioral phenotype. Structural analysis of synaptic inputs revealed a reorganization of presynaptic inputs with a larger proportion of spines being contacted by both excitatory and inhibitory presynaptic terminals. These structural impairments were accompanied by altered excitatory and inhibitory synaptic transmission. Finally, we report that a postnatal treatment of MIA offspring with the anti-inflammatory drug ibudilast, prevented both synaptic and behavioral impairments. Our results suggest that a possible altered inflammatory state associated with maternal immune activation results in impaired synaptic development that persists into adulthood but which can be prevented with early anti-inflammatory treatment.     

Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring

Maternal exposure to viral infection has been associated with an increased risk of schizophrenia in the offspring, and it has been suggested that the maternal immune response may interfere with normal fetal brain development. Although studies in rodents have shown that perinatal viral infections can lead to neuropathological and behavioral abnormalities considered relevant to schizophrenia, it is not clear whether these consequences are due to the infection itself or to the maternal immune response to infection. We show that an induction of maternal immune stimulation without exposure to a virus by injecting pregnant dams with the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I:C) leads to abnormal behavioral and pharmacological responses in the adult offspring. As in schizophrenia, these offspring displayed excessive behavioral switching, manifested in the loss of latent inhibition and in rapid reversal learning. Consistent with the clinical pharmacology of schizophrenia, both deficits were alleviated by antipsychotic treatment. In addition, these offspring displayed increased sensitivity to the locomotor-stimulating effects of MK-801, pointing to developmental alterations of the dopaminergic and/or glutamatergic systems. Prenatal poly I:C administration did not produce learning deficits in classical fear conditioning, active avoidance, discrimination learning and water maze. These results show that the maternal immune response is sufficient to cause behavioral and pharmacological alterations relevant to schizophrenia in the adult offspring.     

Immune activation during mid-gestation disrupts sensorimotor gating in rat offspring

Maternal immune activation (MIA) is a newly developed animal model of schizophrenia. It has recently been reported that when MIA is induced with the cytokine inducer polyinosinic-polycytidilic acid (poly I:C) rats do not show deficits in prepulse inhibition (PPI), a test that is often considered a validity benchmark. The aim of the current experiment was to determine whether doses of poly I:C that have previously been shown to induce the behavioural features of schizophrenia can disrupt PPI in rats. Pregnant rat dams were given a single injection of poly I:C (4.0 mg/kg) or a saline injection equivalent on gestational day 15. Acoustic startle reactivity, habituation of the startle response and PPI were assessed in juvenile (34-35 day) and adult (>56 day) offspring. Prenatal immune activation did not alter startle reactivity on startle-only or prepulse-only trials. Furthermore, there was no effect of MIA on habituation of the startle response. MIA does however disrupt PPI, as PPI was reduced significantly in adult MIA offspring, and a trend was observed in the juvenile animals. Our finding that prenatal poly I:C can disrupt PPI in MIA rats further validates this procedure as an animal model.     

Baseline immunoreactivity before pregnancy and poly(I:C) dose combine to dictate susceptibility and resilience of offspring to maternal immune activation

Despite the potential of rodent models of maternal immune activation (MIA) to identify new biomarkers and therapeutic interventions for a range of psychiatric disorders, current approaches using these models ignore two of the most important aspects of this risk factor for human disease: (i) most pregnancies are resilient to maternal viral infection and (ii) susceptible pregnancies can lead to different combinations of phenotypes in offspring. Here, we report two new sources of variability—the baseline immunoreactivity (BIR) of isogenic females prior to pregnancy and differences in immune responses in C57BL/6 dams across vendors—that contribute to resilience and susceptibility to distinct combinations of behavioral and biological outcomes in offspring. Similar to the variable effects of human maternal infection, MIA in mice does not cause disease-related phenotypes in all pregnancies and a combination of poly(I:C) dose and BIR predicts susceptibility and resilience of pregnancies to aberrant repetitive behaviors and alterations in striatal protein levels in offspring. Even more surprising is that the intermediate levels of BIR and poly(I:C) dose are most detrimental to offspring, with higher BIR and poly(I:C) doses conferring resilience to measured phenotypes in offspring. Importantly, we identify the BIR of female mice as a biomarker before pregnancy that predicts which dams will be most at risk as well as biomarkers in the brains of newborn offspring that correlate with changes in repetitive behaviors. Together, our results highlight considerations for optimizing MIA protocols to enhance rigor and reproducibility and reveal new factors that drive susceptibility of some pregnancies and resilience of others to MIA-induced abnormalities in offspring.     

Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development

Maternal infection is a risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). Indeed, modeling this risk factor in mice through maternal immune activation (MIA) causes ASD- and SZ-like neuropathologies and behaviors in the offspring. Although MIA upregulates pro-inflammatory cytokines in the fetal brain, whether MIA leads to long-lasting changes in brain cytokines during postnatal development remains unknown. Here, we tested this possibility by measuring protein levels of 23 cytokines in the blood and three brain regions from offspring of poly(I:C)- and saline-injected mice at five postnatal ages using multiplex arrays. Most cytokines examined are present in sera and brains throughout development. MIA induces changes in the levels of many cytokines in the brains and sera of offspring in a region- and age-specific manner. These MIA-induced changes follow a few, unexpected and distinct patterns. In frontal and cingulate cortices, several, mostly pro-inflammatory, cytokines are elevated at birth, followed by decreases during periods of synaptogenesis and plasticity, and increases again in the adult. Cytokines are also altered in postnatal hippocampus, but in a pattern distinct from the other regions. The MIA-induced changes in brain cytokines do not correlate with changes in serum cytokines from the same animals. Finally, these MIA-induced cytokine changes are not accompanied by breaches in the blood–brain barrier, immune cell infiltration or increases in microglial density. Together, these data indicate that MIA leads to long-lasting, region-specific changes in brain cytokines in offspring—similar to those reported for ASD and SZ—that may alter CNS development and behavior.     

Maternal immune activation leads to activated inflammatory macrophages in offspring

Several epidemiological studies have shown an association between infection or inflammation during pregnancy and increased risk of autism in the child. In addition, animal models have illustrated that maternal inflammation during gestation can cause autism-relevant behaviors in the offspring; so called maternal immune activation (MIA) models. More recently, permanent changes in T cell cytokine responses were reported in children with autism and in offspring of MIA mice; however, the cytokine responses of other immune cell populations have not been thoroughly investigated in these MIA models. Similar to changes in T cell function, we hypothesized that following MIA, offspring will have long-term changes in macrophage function. To test this theory, we utilized the poly (I:C) MIA mouse model in C57BL/6J mice and examined macrophage cytokine production in adult offspring. Pregnant dams were given either a single injection of 20 mg/kg polyinosinic–polycytidylic acid, poly (I:C), or saline delivered intraperitoneally on gestational day 12.5. When offspring of poly (I:C) treated dams reached 10 weeks of age, femurs were collected and bone marrow-derived macrophages were generated. Cytokine production was measured in bone marrow-derived macrophages incubated for 24 h in either growth media alone, LPS, IL-4/LPS, or IFN-γ/LPS. Following stimulation with LPS alone, or the combination of IFN-γ/LPS, macrophages from offspring of poly (I:C) treated dams produced higher levels of IL-12(p40) (p < 0.04) suggesting an increased M1 polarization. In addition, even without the presence of a polarizing cytokine or LPS stimulus, macrophages from offspring of poly (I:C) treated dams exhibited a higher production of CCL3 (p = 0.05). Moreover, CCL3 levels were further increased when stimulated with LPS, or polarized with either IL-4/LPS or IFN-γ/LPS (p < 0.05) suggesting a general increase in production of this chemokine. Collectively, these data suggest that MIA can produce lasting changes in macrophage function that are sustained into adulthood.     

Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.     

Individual differences in maternal response to immune challenge predict offspring behavior: contribution of environmental factors

Maternal infection during pregnancy elevates risk for schizophrenia and related disorders in offspring. Converging evidence suggests the maternal inflammatory response mediates the interaction between maternal infection, altered brain development, and behavioral outcome. The extent to which individual differences in the maternal response to immune challenge influence the development of these abnormalities is unknown. The present study investigated the impact of individual differences in maternal response to the viral mimic polyinosinic:polycytidylic acid (poly I:C) on offspring behavior. We observed significant variability in body weight alterations of pregnant rats induced by administration of poly I:C on gestational day 14. Furthermore, the presence or absence of maternal weight loss predicted MK-801 and amphetamine stimulated locomotor abnormalities in offspring. MK-801 stimulated locomotion was altered in offspring of all poly I:C treated dams; however, the presence or absence of maternal weight loss resulted in decreased and modestly increased locomotion, respectively. Adult offspring of poly I:C treated dams that lost weight exhibited significantly decreased amphetamine stimulated locomotion, while offspring of poly I:C treated dams without weight loss performed similarly to vehicle controls. Social isolation and increased maternal age predicted weight loss in response to poly I:C but not vehicle injection. In combination, these data identify environmental factors associated with the maternal response to immune challenge and functional outcome of offspring exposed to maternal immune activation.     

Maternal immune activation impairs reversal learning and increases serum tumor necrosis factor-α in offspring

Maternal immune activation (MIA) produces a variety of behavioral and brain abnormalities in rodent models of several neuropsychiatric disorders. However, it remains controversial whether MIA impairs reversal learning, a basic function of flexibility relevant to those diseases, in offspring. In the present study, we used the Morris water maze to investigate the effects of middle to late gestation stage poly(I:C) challenges on spatial learning and subsequent reversal learning performance in adolescent rats. Maternal poly(I:C) treatment induced deficits in reversal learning without affecting spatial acquisition abilities. In addition, the serum level of the proinflammatory cytokine tumor necrosis factor-α was increased in MIA rats. This study advances our understanding of how MIA affects adolescent behavior and brain function.     

The interaction between maternal immune activation and alpha 7 nicotinic acetylcholine receptor in regulating behaviors in the offspring

Mutation of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA7, which encodes the nicotinic acetylcholine receptor alpha 7 subunit (α7nAChR) associated with schizophrenia in clinical studies and rodent models. This study investigates the role of α7nAChR in maternal immune activation (MIA) mice model, a murine model of environmental risk factor for autism and schizophrenia. We provided choline, a selective α7nAChR agonist among its several developmental roles, in the diet of C57BL/6N wild-type dams throughout the gestation and lactation period and induced MIA at mid-gestation. The adult offspring behavior and gene expression profile in the maternal-placental-fetal axis at mid-gestation were investigated. We found that choline supplementation prevented several MIA-induced behavioral abnormalities in the wild-type offspring. Pro-inflammatory cytokine interleukin-6 (Il6) and Chrna7 gene expression in the wild-type fetal brain were elevated by poly(I:C) injection and were suppressed by gestational choline supplementation. We further investigated the gene expression level of Il6 in Chrna7 mutant mice. We found that the basal level of Il6 was higher in Chrna7 mutant fetal brain, which suggests that α7nAChR may serve an anti-inflammatory role in the fetal brain during development. Lastly, we induced MIA in Chrna7^+/− offspring. The Chrna7^+/− offspring were more vulnerable to MIA, with increased behavioral abnormalities. Our study shows that α7nAChR modulates inflammatory response affecting the fetal brain and demonstrates its effects on offspring behavior development after MIA.     

Monocytic Infiltrates Contribute to Autistic-like Behaviors in a Two-Hit Model of Neurodevelopmental Defects

Growing evidence suggests that early-life interactions among genetic, immune, and environment factors may modulate neurodevelopment and cause psycho-cognitive deficits. Maternal immune activation (MIA) induces autism-like behaviors in offspring, but how it interplays with perinatal brain injury (especially birth asphyxia or hypoxia ischemia [HI]) is unclear. Herein we compared the effects of MIA (injection of poly[I:C] to dam at gestational day 12.5), HI at postnatal day 10, and the combined MIA/HI insult in murine offspring of both sexes. We found that MIA induced autistic-like behaviors without microglial activation but amplified post-HI NFκB signaling, pro-inflammatory responses, and brain injury in offspring. Conversely, HI neither provoked autistic-like behaviors nor concealed them in the MIA offspring. Instead, the dual MIA/HI insult added autistic-like behaviors with diminished synaptic density and reduction of autism-related PSD-95 and Homer-1 in the hippocampus, which were missing in the singular MIA or HI insult. Further, the dual MIA/HI insult enhanced the brain influx of Otx2-positive monocytes that are associated with an increase of perineuronal net-enwrapped parvalbumin neurons. Using CCR2-CreER mice to distinguish monocytes from the resident microglia, we found that the monocytic infiltrates gradually adopted a ramified morphology and expressed the microglial signature genes (Tmem119, P2RY12, and Sall1) in post-MIA/HI brains, with some continuing to express the proinflammatory cytokine TNFα. Finally, genetic or pharmacological obstruction of monocytic influx significantly reduced perineuronal net-enwrapped parvalbumin neurons and autistic-like behaviors in MIA/HI offspring. Together, these results suggest a pathologic role of monocytes in the two-hit (immune plus neonatal HI) model of neurodevelopmental defects.SIGNIFICANCE STATEMENT In autism spectrum disorders (ASDs), prenatal infection or maternal immune activation (MIA) may act as a primer for multiple genetic and environmental factors to impair neurodevelopment. This study examined whether MIA cooperates with neonatal cerebral hypoxia ischemia to promote ASD-like aberrations in mice using a novel two-hit model. It was shown that the combination of MIA and neonatal hypoxia ischemia produces autistic-like behaviors in the offspring, and has synergistic effects in inducing neuroinflammation, monocytic infiltrates, synaptic defects, and perineuronal nets. Furthermore, genetic or pharmacological intervention of the MCP1-CCR2 chemoattractant pathway markedly reduced monocytic infiltrates, perineuronal nets, and autistic-like behaviors. These results suggest reciprocal escalation of immune and neonatal brain injury in a subset of ASD that may benefit from monocyte-targeted treatments.     

Altered circadian rhythms in a mouse model of neurodevelopmental disorders based on prenatal maternal immune activation

Individuals with neurodevelopmental disorders, such as schizophrenia and autism spectrum disorder, exhibit various sleep and circadian rhythm disturbances that often persist and worsen throughout the lifespan. To study the interaction between circadian rhythm disruption and neurodevelopmental disorders, we utilized a mouse model based on prenatal maternal immune activation (MIA). We hypothesized that MIA exposure would lead to impaired circadian locomotor activity rhythms in adult mouse offspring. We induced MIA by injecting pregnant dams with polyinosinic:polycytidylic acid (poly IC) at embryonic day 9.5, then aged resulting offspring to adulthood. We first confirmed that poly IC injection in pregnant dams elevated plasma levels of pro- and anti-inflammatory cytokines and chemokines. We then placed adult offspring in running wheels and subjected them to various lighting conditions. Overall, poly IC-exposed male offspring exhibited altered locomotor activity rhythms, reminiscent of individuals with neurodevelopmental disorders. In particular, we report increased (subjective) day activity across 3 different lighting conditions: 12 h of light, 12 h of dark (12:12LD), constant darkness (DD) and constant light. Further data analysis indicated that this was driven by increased activity in the beginning of the (subjective) day in 12:12LD and DD, and at the end of the day in 12:12LD. This effect was sex-dependent, as in utero poly IC exposure led overall to much milder alterations in locomotor activity rhythms in female offspring than in male offspring. We also confirmed that the observed behavioral impairments in adult poly IC-exposed offspring were not due to differences in maternal behavior. These data further our understanding of the link between circadian rhythm disruption and neurodevelopmental disorders and may have implications for mitigating risk to the disorders and/or informing the development of circadian-based therapies.     

Alterations in cognitive function and behavioral response to amphetamine induced by prenatal inflammation are dependent on the stage of pregnancy

Maternal infection during human pregnancy has been associated with the development of schizophrenia in the adult offspring. The stage of development and the maternal inflammatory response to infection, which undergoes quantitative and qualitative changes throughout gestation, are thought to determine critical windows of vulnerability for the developing brain. In order to investigate how these two factors may contribute to the outcome in the offspring, we studied the inflammatory response to turpentine (TURP) injection (100 μl/dam) and its consequences in the adult offspring, in pregnant rats at gestational day (GD) 15 or 18, which correspond to late first and early second trimester of human pregnancy, respectively. Maternal inflammatory response to TURP was different between the two GDs, with fever and circulating levels of the pro-inflammatory interleukin (IL)-6 significantly attenuated at GD 18, compared to GD 15. In the adult offspring, TURP challenge at GD 15 induced a significant decrease in pre-pulse inhibition (PPI) of acoustic startle, increased latency in the cued task of the Morris-water maze, prolonged conditioned fear response and enhanced locomotor effect of amphetamine. In contrast, the same immune challenge at GD 18 induced only a prolonged conditioned fear response. These results suggest a window of vulnerability at GD 15, at which TURP seems to affect several behaviors that are strongly modulated by dopamine. This was supported by increased tyrosine hydroxylase expression in the nucleus accumbens of the adult offspring of mothers treated at GD 15.     

Differential effects of maternal immune activation and juvenile stress on anxiety-like behaviour and physiology in adult rats: no evidence for the "double-hit hypothesis"

Environmental disruptions can influence neurodevelopment during pre- and postnatal periods. Given such a large time window of opportunity for insult, the “double-hit hypothesis” proposes that exposure to an environmental challenge may impact development such that an individual becomes vulnerable to developing a psychopathology, which then manifests upon exposure to a second challenge later in life. The present study in male rats utilized the framework of the “double-hit hypothesis” to investigate potential compounding effects of maternal immune activation (MIA) during pregnancy and exposure of offspring to stress during juvenility on physiological and behavioural indications of anxiety in adulthood. We used an established rat model of MIA via maternal treatment with polyinosinic:polycytidylic acid (poly I:C) on gestation day 15 in combination with a model of juvenile stress (applied ages 27-29 d) in offspring to explore potential interacting/additive effects. First, we confirmed our employment of the MIA model by replicating previous findings that prenatal treatment with poly I:C caused deficits in sensorimotor gating in adult offspring, as measured by prepulse inhibition. Juvenile stress, on the other hand, had no effect on prepulse inhibition. In terms of anxiety-related behaviour and physiology, we found that prenatal poly I:C alone or in combination with juvenile stress had no effects on body weight, adrenal weight, and plasma concentration of corticosterone and cytokines in adult rats. MIA and juvenile stress increased anxiety-related behaviour on the elevated plus maze, but did so independently of each other. In all, our findings do not support an interaction between MIA and juvenile stress in terms of producing marked changes related to anxiety-like behaviour in adulthood.     

Effects of risperidone treatment in adolescence on hippocampal neurogenesis, parvalbumin expression, and vascularization following prenatal immune activation in rats

Maternal infection in pregnancy is an environmental risk factor for the development of schizophrenia and related disorders in the offspring, and this association is recapitulated in animal models using gestational infection or immune stimulation. We have recently shown that behavioral abnormalities and altered hippocampal morphology emerging in adult offspring of dams treated with the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) are prevented by treatment with the atypical antipsychotic drug risperidone (RIS) in adolescence. Here we used a battery of cellular markers and Nissl stain to morphometrically analyze different hippocampal cell populations in the offspring of poly I:C and saline-treated mothers that received saline or RIS in adolescence, at different time points of postnatal development. We report that impaired neurogenesis, disturbed micro-vascularization and loss of parvalbumin-expressing hippocampal interneurons, are found in the offspring of poly I:C-treated dams. Most, but not all, of these neuropathological changes are not present in poly I:C offspring that had been treated with RIS. These effects may be part of the complex processes underlying the capacity of RIS treatment in adolescence to prevent structural and behavioral abnormalities deficits in the poly I:C offspring.     

Maternal immune activation during pregnancy impacts on brain structure and function in the adult offspring

Gestational infection constitutes a risk factor for the occurrence of psychiatric disorders in the offspring. Activation of the maternal immune system (MIA) with subsequent impact on the development of the fetal brain is considered to form the neurobiological basis for aberrant neural wiring and the psychiatric manifestations later in offspring life. The examination of validated animal models constitutes a premier resource for the investigation of the neural underpinnings.Here we used a mouse model of MIA based upon systemic treatment of pregnant mice with Poly(I:C) (polyriboinosinic-polyribocytidilic acid), for the unbiased and comprehensive analysis of the impact of MIA on adult offspring brain activity, morphometry, connectivity and function by a magnetic resonance imaging (MRI) approach.Overall lower neural activity, smaller brain regions and less effective fiber structure were observed for Poly(I:C) offspring compared to the control group. The corpus callosum was significantly smaller and presented with a disruption in myelin/ fiber structure in the MIA progeny. Subsequent resting-state functional MRI experiments demonstrated a paralleling dysfunctional interhemispheric connectivity. Additionally, while the overall flow of information was intact, cortico-limbic connectivity was hampered and limbic circuits revealed hyperconnectivity in Poly(I:C) offspring.Our study sheds new light on the impact of maternal infection during pregnancy on the offspring brain and identifies aberrant resting-state functional connectivity patterns as possible correlates of the behavioral phenotype with relevance for psychiatric disorders.