Based on the epidemiological association between maternal infection during pregnancy and enhanced risk of neurodevelopmental brain disorders in the offspring, a number of in-vivo models have been ...established in rats and mice in order to study this link on an experimental basis. These models provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, and to explore the critical neuroimmunological and developmental factors involved in shaping the vulnerability to infection-induced neurodevelopmental disturbances in humans. Here, we summarize the findings derived from numerous in-vivo models of prenatal infection and/or immune activation in rats and mice, including models of exposure to influenza virus, bacterial endotoxin, viral-like acute phase responses and specific pro-inflammatory cytokines. Furthermore, we discuss the methodological aspects of these models in relation to their practical implementation and their translatability to the human condition. We highlight that these models can successfully examine the influence of the precise timing of maternal immune activation, the role of pro- and anti-inflammatory cytokines, and the contribution of gene–environment interactions in the association between prenatal immune challenge and postnatal brain dysfunctions. Finally, we discuss that in-vivo models of prenatal immune activation offer a unique opportunity to establish and evaluate early preventive interventions aiming to reduce the risk of long-lasting brain dysfunctions following prenatal exposure to infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
While multiple theories have been put forth regarding the origin of schizophrenia, by far the vast majority of evidence points to the neurodevelopmental model in which developmental insults as early ...as late first or early second trimester lead to the activation of pathologic neural circuits during adolescence or young adulthood leading to the emergence of positive or negative symptoms. In this report, we examine the evidence from brain pathology (enlargement of the cerebroventricular system, changes in gray and white matters, and abnormal laminar organization), genetics (changes in the normal expression of proteins that are involved in early migration of neurons and glia, cell proliferation, axonal outgrowth, synaptogenesis, and apoptosis), environmental factors (increased frequency of obstetric complications and increased rates of schizophrenic births due to prenatal viral or bacterial infections), and gene-environmental interactions (a disproportionate number of schizophrenia candidate genes are regulated by hypoxia, microdeletions and microduplications, the overrepresentation of pathogen-related genes among schizophrenia candidate genes) in support of the neurodevelopmental model. We relate the neurodevelopmental model to a number of findings about schizophrenia. Finally, we also examine alternate explanations of the origin of schizophrenia including the neurodegenerative model.
Reelin is a glycoprotein that serves important roles both during development (regulation of neuronal migration and brain lamination) and in adulthood (maintenance of synaptic function). A number of ...neuropsychiatric disorders including autism, schizophrenia, bipolar disorder, major depression, Alzheimer's disease and lissencephaly share a common feature of abnormal Reelin expression in the brain. Altered Reelin expression has been hypothesized to impair neuronal connectivity and synaptic plasticity, leading ultimately to the cognitive deficits present in these disorders. The mechanisms for abnormal Reelin expression in some of these disorders are currently unknown although possible explanations include early developmental insults, mutations, hypermethylation of the promoter for the Reelin gene (RELN), miRNA silencing of Reelin mRNA, FMRP underexpression and Reelin processing abnormalities. Increasing Reelin expression through pharmacological therapies may help ameliorate symptoms resulting from Reelin deficits.
This article is part of the Special Issue entitled ‘Neurodevelopmental Disorders’.
► Reelin plays important roles in neuronal migration and brain development. ► Reelin is an important modulator of synaptic function. ► Reelin expression is altered in disorders such as schizophrenia and autism. ► Reelin is an important potential therapeutic target.
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GEOZS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Schizophrenia is a severe neurodevelopmental disorder with genetic and environmental etiologies. Prenatal viral/bacterial infections and inflammation play major roles in the genesis of schizophrenia. ...In this review, we describe a viral model of schizophrenia tested in mice whereby the offspring of mice prenatally infected with influenza at E7, E9, E16, and E18 show significant gene, protein, and brain structural abnormalities postnatally. Similarly, we describe data on rodents exposed to bacterial infection or injected with a synthetic viral mimic (PolyI:C) also demonstrating brain structural and behavioral abnormalities. Moreover, human serologic data has been indispensible in supporting the viral theory of schizophrenia. Individuals born seropositive for bacterial and viral agents are at a significantly elevated risk of developing schizophrenia. While the specific mechanisms of prenatal viral/bacterial infections and brain disorder are unclear, recent findings suggest that the maternal inflammatory response may be associated with fetal brain injury. Preventive and therapeutic treatment options are also proposed. This review presents data related to epidemiology, human serology, and experimental animal models which support the viral model of schizophrenia.
► Prenatal viral infections cause abnormal brain development in animals and humans. ► Up to 10–20% of schizophrenia cases may be caused by infectious etiologies. ► Adjunctive anti-viral/anti-inflammatory agents may treat/prevent schizophrenia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Gamma-aminobutyric acid A (GABA
A
) receptors are ligand-gated ion channels responsible for mediation of fast inhibitory action of GABA in the brain. Preliminary reports have demonstrated altered ...expression of GABA receptors in the brains of subjects with autism suggesting GABA/glutamate system dysregulation. We investigated the expression of four GABA
A
receptor subunits and observed significant reductions in GABRA1, GABRA2, GABRA3, and GABRB3 in parietal cortex (Brodmann’s Area 40 (BA40)), while GABRA1 and GABRB3 were significantly altered in cerebellum, and GABRA1 was significantly altered in superior frontal cortex (BA9). The presence of seizure disorder did not have a significant impact on GABA
A
receptor subunit expression in the three brain areas. Our results demonstrate that GABA
A
receptors are reduced in three brain regions that have previously been implicated in the pathogenesis of autism, suggesting widespread GABAergic dysfunction in the brains of subjects with autism.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Abstract Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABAergic receptor abnormalities have been documented in several major psychiatric disorders including ...schizophrenia, mood disorders, and autism. Abnormal expression of mRNA and protein for multiple GABA receptors has also been observed in multiple brain regions leading to alterations in the balance between excitatory/inhibitory signaling in the brain with potential profound consequences for normal cognition and maintenance of mood and perception. Altered expression of GABAA receptor subunits has been documented in fragile X mental retardation 1 (FMR1) knockout mice, suggesting that loss of its protein product, fragile X mental retardation protein (FMRP), impacts GABAA subunit expression. Recent postmortem studies from our laboratory have shown reduced expression of FMRP in the brains of subjects with schizophrenia, bipolar disorder, major depression, and autism. FMRP acts as a translational repressor and, under normal conditions, inhibits metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. In fragile X syndrome (FXS), the absence of FMRP is hypothesized to lead to unregulated mGluR5 signaling, ultimately resulting in the behavioral and intellectual impairments associated with this disorder. Our laboratory has identified changes in mGluR5 expression in autism, schizophrenia, and mood disorders. In the current review article, we discuss our postmortem data on GABA receptors, FMRP, and mGluR5 levels and compare our results with other laboratories. Finally, we discuss the interactions between these molecules and the potential for new therapeutic interventions that target these interconnected signaling systems.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Autism spectrum disorder (ASD) is a developmental disorder with a rising prevalence and unknown etiology presenting with deficits in cognition and abnormal behavior. We hypothesized that the ...investigation of the synaptic component of prefrontal cortex may provide proteomic signatures that may identify the biological underpinnings of cognitive deficits in childhood ASD. Subcellular fractions of synaptosomes from prefrontal cortices of age-, brain area-, and postmortem-interval-matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of data revealed the enrichment of ASD risk genes that participate in slow maturation of the postsynaptic density (PSD) structure and function during early brain development. Proteomic analysis revealed down regulation of PSD-related proteins including AMPA and NMDA receptors, GRM3, DLG4, olfactomedins, Shank1-3, Homer1, CaMK2α, NRXN1, NLGN2, Drebrin1, ARHGAP32, and Dock9 in children with autism (FDR-adjusted P < 0.05). In contrast, PSD-related alterations were less severe or unchanged in adult individuals with ASD. Network analyses revealed glutamate receptor abnormalities. Overall, the proteomic data support the concept that idiopathic autism is a synaptopathy involving PSD-related ASD risk genes. Interruption in evolutionarily conserved slow maturation of the PSD complex in prefrontal cortex may lead to the development of ASD in a susceptible individual.
Abstract Postmortem and genetic studies have clearly demonstrated changes in GABAB receptors in neuropsychiatric disorders such as autism, bipolar disorder, major depression, and schizophrenia. ...Moreover, a number of recent studies have stressed the importance of cerebellar dysfunction in these same disorders. In the current study, we examined protein levels of the two GABAB receptor subunits GABBR1 and GABBR2 in lateral cerebella from a well-characterized cohort of subjects with schizophrenia (n = 15), bipolar disorder (n = 14), major depression (n = 13) and healthy controls (n = 12). We found significant reductions in protein for both GABBR1 and GABBR2 in lateral cerebella from subjects with schizophrenia, bipolar disorder and major depression when compared with controls. These results provide further evidence of GABAergic dysfunction in these three disorders as well as identify potential targets for therapeutic intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Prenatal viral infection has been associated with development of schizophrenia and autism. Our laboratory has previously shown that viral infection causes deleterious effects on brain ...structure and function in mouse offspring following late first trimester (E9) administration of influenza virus. We hypothesized that late second trimester infection (E18) in mice may lead to a different pattern of brain gene expression and structural defects in the developing offspring. C57BL6J mice were infected on E18 with a sublethal dose of human influenza virus or sham-infected using vehicle solution. Male offsping of the infected mice were collected at P0, P14, P35 and P56, their brains removed and prefrontal cortex, hippocampus and cerebellum dissected and flash frozen. Microarray, qRT-PCR, DTI and MRI scanning, western blotting and neurochemical analysis were performed to detect differences in gene expression and brain atrophy. Expression of several genes associated with schizophrenia or autism including Sema3a, Trfr2 and Vldlr were found to be altered as were protein levels of Foxp2. E18 infection of C57BL6J mice with a sublethal dose of human influenza virus led to significant gene alterations in frontal, hippocampal and cerebellar cortices of developing mouse progeny. Brain imaging revealed significant atrophy in several brain areas and white matter thinning in corpus callosum. Finally, neurochemical analysis revealed significantly altered levels of serotonin (P14, P35), 5-Hydroxyindoleacetic acid (P14) and taurine (P35). We propose that maternal infection in mouse provides an heuristic animal model for studying the environmental contributions to genesis of schizophrenia and autism, two important examples of neurodevelopmental disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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