Individuals with schizophrenia have increased humoral immunity to infectious and food antigens. Increased complement activation and increased levels of circulating immune complexes (CIC) are found in individuals with this disease. The complement factor C1q that binds these complexes is also highly expressed at synaptic locations in the developing cortex. Project 6 will test the hypothesis that DISC1 mutant mice display increased C1q activation in the brain. Furthermore, we predict that early postnatal exposure to an environmental trigger such as Toxoplasma gondii infection will further exacerbate C1q activation in the brain of DISC1 mutant mice to contribute to GABA interneuron and spine density deficits in the developing frontal cortex. Extensive case-controlled collections of blood and CSF taken at various stages of disease in conjunction with matched post-mortem serum and frontal cortex samples will allow parallel studies of human samples with DISC1 mutant mice.
Specific Aim 1 will test the hypothesis that following penetration of a model antigen, casein, through the GI barrier, C1q-associated immune complexes are formed, leaving molecular signatures in human samples that are traceable from the periphery to the CNS.
Specific Aim 2 will evaluate the hypothesis that CIS-related activation of the complement system in the brain of DISC1 mutant mice will be exacerbated by early postnatal infection with Toxoplasma gondii, leading to abnormal development of GABA interneuron and dendritic spines in the frontal cortex.

Public Health Relevance

This study integrates clinical and basic science to determine how environmental triggers of the immune response are applicable to schizophrenia. Peripheral and CNS molecular signatures gleaned from human samples will be used to develop biomarkers, and DISC1 mutant mouse studies will allow testing of how the proposed gene-environmental model may impact CNS immune activation during development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH094268-04
Application #
8681537
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
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