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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1)
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Johns Hopkins University
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