Activation of the maternal immune system alters cerebellar development in the offspring, Brain Behav Immun 23, 116-123

Biology Division, California Institute of Technology, 391 S. Holliston Avenue, M/C 216-76 Pasadena, CA 91125, USA.
Brain Behavior and Immunity (Impact Factor: 5.89). 09/2008; 23(1):116-23. DOI: 10.1016/j.bbi.2008.07.012
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A common pathological finding in autism is a localized deficit in Purkinje cells (PCs). Cerebellar abnormalities have also been reported in schizophrenia. Using a mouse model that exploits a known risk factor for these disorders, maternal infection, we asked if the offspring of pregnant mice given a mid-gestation respiratory infection have cerebellar pathology resembling that seen in these disorders. We also tested the effects of maternal immune activation in the absence of virus by injection of the synthetic dsRNA, poly(I:C). We infected pregnant mice with influenza on embryonic day 9.5 (E9.5), or injected poly(I:C) i.p. on E12.5, and assessed the linear density of PCs in the cerebellum of adult or postnatal day 11 (P11) offspring. To study granule cell migration, we also injected BrdU on P11. Adult offspring of influenza- or poly(I:C)-exposed mice display a localized deficit in PCs in lobule VII of the cerebellum, as do P11 offspring. Coincident with this are heterotopic PCs, as well as delayed migration of granule cells in lobules VI and VII. The cerebellar pathology observed in the offspring of influenza- or poly(I:C)-exposed mice is strikingly similar to that observed in autism. The poly(I:C) findings indicate that deficits are likely caused by the activation of the maternal immune system. Finally, our data suggest that cerebellar abnormalities occur during embryonic development, and may be an early deficit in autism and schizophrenia.

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Available from: Natalia V Malkova,
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    • "Again, exposure around the time of closure of the neural tube seems to be related to the onset of autistic-like behaviors in the offspring. For instance, injection of poly I:C on gestational day 9.5 or 12.5 caused impairments in social interaction and anxiety behaviors in the offspring (Shi et al., 2003; Smith et al., 2007; Hsiao and Patterson, 2011), together with altered cerebellar development (Shi et al., 2009). Furthermore, injection of poly I:C on gestational days 10.5, 12.5, and 14.5 induced qualitative and quantitative differences in pup isolation-induced USV emission, together with decreased sociability and repetitive/stereotyped behavior in both marble burying and self-grooming tests at adulthood (Malkova et al., 2012). "
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    ABSTRACT: Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets.
    Behavioural pharmacology 09/2015; 26(6):522-540. DOI:10.1097/FBP.0000000000000163 · 2.15 Impact Factor
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    • "To determine to what extent MIA evoked by poly ( I : C ) can alter cortex invasion by microglia and / or change embryonic microglial cell activation state , we evoked MIA using a single ( at E11 . 5 ) or a double injection ( at E11 . 5 and E15 . 5 ) of poly ( I : C ) ( Meyer et al . , 2006 ; Shi et al . , 2009 ) . This developmental time window is an important time point for cortex invasion by immature microglia as their cell density dramatically increases during this period ( Swinnen et al . , 2013 ) . We show that poly ( I : C ) - induced MIA does not affect microglial density and activation level during embryonic development suggesting tha"
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    ABSTRACT: Several studies have indicated that inflammation during pregnancy increases the risk for the development of neuropsychiatric disorders in the offspring. Morphological brain abnormalities combined with deviations in the inflammatory status of the brain can be observed in patients of both autism and schizophrenia. It was shown that acute infection can induce changes in maternal cytokine levels which in turn are suggested to affect fetal brain development and increase the risk on the development of neuropsychiatric disorders in the offspring. Animal models of maternal immune activation reproduce the etiology of neurodevelopmental disorders such as schizophrenia and autism. In this study the poly (I:C) model was used to mimic viral immune activation in pregnant mice in order to assess the activation status of fetal microglia in these developmental disorders. Because microglia are the resident immune cells of the brain they were expected to be activated due to the inflammatory stimulus. Microglial cell density and activation level in the fetal cortex and hippocampus were determined. Despite the presence of a systemic inflammation in the pregnant mice, there was no significant difference in fetal microglial cell density or immunohistochemically determined activation level between the control and inflammation group. These data indicate that activation of the fetal microglial cells is not likely to be responsible for the inflammation induced deficits in the offspring in this model.
    Frontiers in Cellular Neuroscience 08/2015; 9:301. DOI:10.3389/fncel.2015.00301 · 4.29 Impact Factor
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    • "Deficits in PPI of the acoustic startle response are a stable cross-species phenomenon that is used as a hallmark measure of schizotypal behavioral deficits in animal models of schizophrenia. Reductions in PPI have repeatedly been shown in the MIA model, across both mice and rats, across varying doses and gestational timing of the insult (Meyer et al., 2006b, 2008b; Nyffeler et al., 2006; Ozawa et al., 2006; Smith et al., 2007; Wolff and Bilkey, 2008; Shi et al., 2009). In mice, PPI deficits present with a post-pubertal onset (Ozawa et al., 2006; Vuillermot et al., 2010), and the deficit has been shown by our lab to be present in both juvenile (Wolff and Bilkey, 2010) and adult rats (Wolff and Bilkey, 2008); a finding that is consistent with data showing PPI deficits in both prodromal presentation (Quednow et al., 2008) and individuals at high-risk for schizophrenia (Cadenhead et al., 2000; Kumari et al., 2008). "
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    ABSTRACT: Maternal exposure to infection occurring mid-gestation produces a three-fold increase in the risk of schizophrenia in the offspring. The critical initiating factor appears to be the maternal immune activation (MIA) that follows infection. This process can be induced in rodents by exposure of pregnant dams to the viral mimic Poly I:C, which triggers an immune response that results in structural, functional, behavioral, and electrophysiological phenotypes in the adult offspring that model those seen in schizophrenia. We used this model to explore the role of synchronization in brain neural networks, a process thought to be dysfunctional in schizophrenia and previously associated with positive, negative, and cognitive symptoms of schizophrenia. Exposure of pregnant dams to Poly I:C on GD15 produced an impairment in long-range neural synchrony in adult offspring between two regions implicated in schizophrenia pathology; the hippocampus and the medial prefrontal cortex (mPFC). This reduction in synchrony was ameliorated by acute doses of the antipsychotic clozapine. MIA animals have previously been shown to have impaired pre-pulse inhibition (PPI), a gold-standard measure of schizophrenia-like deficits in animal models. Our data showed that deficits in synchrony were positively correlated with the impairments in PPI. Subsequent analysis of LFP activity during the PPI response also showed that reduced coupling between the mPFC and the hippocampus following processing of the pre-pulse was associated with reduced PPI. The ability of the MIA intervention to model neurodevelopmental aspects of schizophrenia pathology provides a useful platform from which to investigate the ontogeny of aberrant synchronous processes. Further, the way in which the model expresses translatable deficits such as aberrant synchrony and reduced PPI will allow researchers to explore novel intervention strategies targeted to these changes.
    Frontiers in Behavioral Neuroscience 12/2013; 7:217. DOI:10.3389/fnbeh.2013.00217 · 3.27 Impact Factor
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