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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Severance, Emily G; Gressitt, Kristin L; Stallings, Cassie R et al. (2016) Probiotic normalization of Candida albicans in schizophrenia: A randomized, placebo-controlled, longitudinal pilot study. Brain Behav Immun :
Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48
Severance, Emily G; Gressitt, Kristin L; Stallings, Catherine R et al. (2016) Candida albicans exposures, sex specificity and cognitive deficits in schizophrenia and bipolar disorder. NPJ Schizophr 2:16018
Severance, Emily G; Yolken, Robert H; Eaton, William W (2016) Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Schizophr Res 176:23-35
Saito, A; Taniguchi, Y; Rannals, M D et al. (2016) Early postnatal GABAA receptor modulation reverses deficits in neuronal maturation in a conditional neurodevelopmental mouse model of DISC1. Mol Psychiatry 21:1449-59
Katsanis, Nicholas (2016) The continuum of causality in human genetic disorders. Genome Biol 17:233
Tankou, Stephanie; Ishii, Kazuhiro; Elliott, Christina et al. (2016) SUMOylation of DISC1: a potential role in neural progenitor proliferation in the developing cortex. Mol Neuropsychiatry 2:20-27
Macpherson, Tom; Morita, Makiko; Wang, Yanyan et al. (2016) Nucleus accumbens dopamine D2-receptor expressing neurons control behavioral flexibility in a place discrimination task in the IntelliCage. Learn Mem 23:359-64
Koh, Ming Teng; Shao, Yi; Sherwood, Andrew et al. (2016) Impaired hippocampal-dependent memory and reduced parvalbumin-positive interneurons in a ketamine mouse model of schizophrenia. Schizophr Res 171:187-94
Owen, Michael J; Sawa, Akira; Mortensen, Preben B (2016) Schizophrenia. Lancet 388:86-97

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