Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH094268-03
Application #
8515809
Study Section
Special Emphasis Panel (ZMH1-ERB-S)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$228,115
Indirect Cost
$88,965

  Institution

Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Uehara, Maiko; Tabata, Eri; Ishii, Kazuhiro et al. (2018) Chitinase mRNA Levels Determined by QPCR in Crab-Eating Monkey (Macaca fascicularis) Tissues: Species-Specific Expression of Acidic Mammalian Chitinase and Chitotriosidase. Genes (Basel) 9:
Posporelis, Sotirios; Coughlin, Jennifer M; Marsman, Anouk et al. (2018) Decoupling of Brain Temperature and Glutamate in Recent Onset of Schizophrenia: A 7T Proton Magnetic Resonance Spectroscopy Study. Biol Psychiatry Cogn Neurosci Neuroimaging 3:248-254
Zhu, Xiaolei; Nedelcovych, Michael T; Thomas, Ajit G et al. (2018) JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress. Neuropsychopharmacology :
Avramopoulos, Dimitrios (2018) Neuregulin 3 and its roles in schizophrenia risk and presentation. Am J Med Genet B Neuropsychiatr Genet 177:257-266
Sumitomo, Akiko; Horike, Kouta; Hirai, Kazuko et al. (2018) A mouse model of 22q11.2 deletions: Molecular and behavioral signatures of Parkinson's disease and schizophrenia. Sci Adv 4:eaar6637
Severance, Emily G; Dickerson, Faith B; Yolken, Robert H (2018) Autoimmune phenotypes in schizophrenia reveal novel treatment targets. Pharmacol Ther 189:184-198
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 :

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