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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH094268-01
Application #
8275460
Study Section
Special Emphasis Panel (ZMH1-ERB-S (02))
Project Start
Project End
Budget Start
2011-07-12
Budget End
2012-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$246,000
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Fukudome, Daisuke; Hayes, Lindsay N; Faust, Travis E et al. (2018) Translocator protein (TSPO) and stress cascades in mouse models of psychosis with inflammatory disturbances. Schizophr Res :
Prandovszky, Emese; Li, Ye; Sabunciyan, Sarven et al. (2018) Toxoplasma gondii-Induced Long-Term Changes in the Upper Intestinal Microflora during the Chronic Stage of Infection. Scientifica (Cairo) 2018:2308619
Sumitomo, Akiko; Saka, Ayumi; Ueta, Keisho et al. (2018) Methylphenidate and Guanfacine Ameliorate ADHD-Like Phenotypes in Fez1-Deficient Mice. Mol Neuropsychiatry 3:223-233
Weber, Natalya S; Gressitt, Kristin L; Cowan, David N et al. (2018) Monocyte activation detected prior to a diagnosis of schizophrenia in the US Military New Onset Psychosis Project (MNOPP). Schizophr Res :
Torniainen-Holm, Minna; Suvisaari, Jaana; Lindgren, Maija et al. (2018) Association of cytomegalovirus and Epstein-Barr virus with cognitive functioning and risk of dementia in the general population: 11-year follow-up study. Brain Behav Immun 69:480-485
Li, Ye; Viscidi, Raphael P; Kannan, Geetha et al. (2018) Chronic Toxoplasma gondii Infection Induces Anti-N-Methyl-d-Aspartate Receptor Autoantibodies and Associated Behavioral Changes and Neuropathology. Infect Immun 86:
Lindgren, Maija; Torniainen-Holm, Minna; Härkänen, Tommi et al. (2018) The association between toxoplasma and the psychosis continuum in a general population setting. Schizophr Res 193:329-335
Sedlak, Thomas W; Nucifora, Leslie G; Koga, Minori et al. (2018) Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study. Mol Neuropsychiatry 3:214-222
McFarland, Ross; Wang, Zi Teng; Jouroukhin, Yan et al. (2018) AAH2 gene is not required for dopamine-dependent neurochemical and behavioral abnormalities produced by Toxoplasma infection in mouse. Behav Brain Res 347:193-200
Severance, Emily G; Yolken, Robert H (2018) Deciphering microbiome and neuroactive immune gene interactions in schizophrenia. Neurobiol Dis :

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