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 #
5P50MH094268-02
Application #
8377462
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$241,844
Indirect Cost
$94,337
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Tanaka, Motomasa; Ishizuka, Koko; Nekooki-Machida, Yoko et al. (2017) Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington's disease. J Clin Invest 127:1438-1450
Koh, Ming Teng; Shao, Yi; Rosenzweig-Lipson, Sharon et al. (2017) Treatment with levetiracetam improves cognition in a ketamine rat model of schizophrenia. Schizophr Res :
Dickerson, Faith; Severance, Emily; Yolken, Robert (2017) The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun 62:46-52
Nucifora Jr, Frederick C; Mihaljevic, Marina; Lee, Brian J et al. (2017) Clozapine as a Model for Antipsychotic Development. Neurotherapeutics 14:750-761
Lavoie, Joëlle; Gassó Astorga, Patricia; Segal-Gavish, Hadar et al. (2017) The Olfactory Neural Epithelium As a Tool in Neuroscience. Trends Mol Med 23:100-103
Yoshimura, Atsushi; Goodson, Carrie; Johns, Jordan T et al. (2017) Altered cortical brain activity in end stage liver disease assessed by multi-channel near-infrared spectroscopy: Associations with delirium. Sci Rep 7:9258
Suvisaari, Jaana; Torniainen-Holm, Minna; Lindgren, Maija et al. (2017) Toxoplasma gondii infection and common mental disorders in the Finnish general population. J Affect Disord 223:20-25
Sagata, Noriaki; Kato, Takahiro A; Kano, Shin-Ichi et al. (2017) Dysregulated gene expressions of MEX3D, FOS and BCL2 in human induced-neuronal (iN) cells from NF1 patients: a pilot study. Sci Rep 7:13905
Nishi, Akira; Numata, Shusuke; Tajima, Atsushi et al. (2017) De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity. Sci Rep 7:2887
Namkung, Ho; Kim, Sun-Hong; Sawa, Akira (2017) The Insula: An Underestimated Brain Area in Clinical Neuroscience, Psychiatry, and Neurology. Trends Neurosci 40:200-207

Showing the most recent 10 out of 164 publications