The pathogenesis of schizophrenia is likely to involve multiple interactions between genetic vulnerability and environmental factors. Among non-genetic factors, microbial infections have been associated with the increased incidence of mental diseases. We believe that experimental models based on identified genetic mutations and measurable environment factors can significantly advance our understanding of the mechanisms of gene-environment interactions (GEI) relevant to schizophrenia. The main goal of Project 5 is to characterize new mouse models of GEI based on the genes that are identified by Projects 1-4, interact with DISC1, and have been associated with schizophrenia. We will evaluate the neurobehavioral effects and molecular biomarkers of GEI in mice exposed to either maternal immune activation or early postnatal chronic infection with Toxoplasma gondii. We predict that genetic manipulations in DISC1 and/or its partners will synergistically interact with relevant environmental factors to produce the neurobehavioral and molecular alterations consistent with aspects of schizophrenia and related mental disorders.
Specific Aim 1 will test the hypothesis that prenatal interaction of immune activation and mutant DISC1 will synergistically lead to schizophrenia-like neurobehavioral abnormalities in adult offspring.
Specific Aim 2 will test the hypothesis that early postnatal interactions between chronic infection with Toxoplasma gondii and mutant DISC1 will synergistically produce the neurobehavioral abnormalities resembling positive and cognitive symptoms of schizophrenia. In addtion, in collaboration with Project 6, we will evaluate a role of immunocomplexes in the neurobehavioral pathology in Toxoplasma-infected DISCI mutant mice.
Specific Aim 3 will identify the gene expression signatures of gene-environment interactions. The project will characterize the neurobehavioral and molecular consequences of GEI relevant to schizophrenia. The results will help identify the specific molecular pathways that may mediate interplay between the genetic mutations and environmental insults in the pathogenesis of schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-S)
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Johns Hopkins University
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Shahani, N; Seshadri, S; Jaaro-Peled, H et al. (2015) DISC1 regulates trafficking and processing of APP and A? generation. Mol Psychiatry 20:874-9
Xiao, J; Li, Y; Prandovszky, E et al. (2014) MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway. Neuroscience 268:128-38
Dada, Tahani; Rosenzweig, Jason M; Al Shammary, Mofeedah et al. (2014) Mouse model of intrauterine inflammation: sex-specific differences in long-term neurologic and immune sequelae. Brain Behav Immun 38:142-50
Bernier, Raphael; Golzio, Christelle; Xiong, Bo et al. (2014) Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158:263-76
Abazyan, Sofya; Yang, Eun Ju; Abazyan, Bagrat et al. (2014) Mutant disrupted-in-schizophrenia 1 in astrocytes: focus on glutamate metabolism. J Neurosci Res 92:1659-68
Posporelis, Sotirios; Sawa, Akira; Smith, Gwenn S et al. (2014) Promoting careers in academic research to psychiatry residents. Acad Psychiatry 38:185-90
Xia, Meng; Abazyan, Sofya; Jouroukhin, Yan et al. (2014) Behavioral sequelae of astrocyte dysfunction: focus on animal models of schizophrenia. Schizophr Res :
Severance, Emily G; Gressitt, Kristin L; Yang, Shuojia et al. (2014) Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder. Bipolar Disord 16:230-40
Severance, Emily G; Gressitt, Kristin L; Buka, Stephen L et al. (2014) Maternal complement C1q and increased odds for psychosis in adult offspring. Schizophr Res 159:14-9
Hayashi-Takagi, Akiko; Araki, Yoichi; Nakamura, Mayumi et al. (2014) PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence. Proc Natl Acad Sci U S A 111:6461-6

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