Maternal Immune Activation (MIA) results from viral infection during pregnancy and is the best characterized non-genetic risk factor for schizophrenia. We and others have developed a mouse model of MIA that produces neurobiological and behavioral deficits that resemble those of schizophrenia. The MIA model, unlike the Center's other animal modes, makes no suppositions about the role of alpha7 nicotinic acetylcholine receptors. Therefore, it is an excellent model to test the effects of perinatal choline to determine if this intervention is effective in a model that does not pre-suppose diminished alpha7 nicotinic receptors. MIA is often hypothesized to interact with genetic risk for schizophrenia, so that its most marked effects are in genetically vulnerable individuals. Therefore, in a second aim, we will test whether its effects are enhanced in dams and fetuses who are heterozygous for the Chrna7 null mutation. We hypothesize that there may be additive effects of fetal genotype and the MIA insult. In addition, the dam's genotype may be influential in regulating MIA, because alpha7 nicotinic receptors have been shown to play a role in the moderation of inflammatory responses. Project 6 thus introduces a new model to the Center, which will influence Project 2's clinical research on the possible maternal causes of sensory gating abnormalities in infants, as well as Project 1's investigation of which adult patients respond to nicotinic agonist therapies. Project 6 will receive genetic analysis support from Project 3, phenotyping support from Project 4, and will assess MIA in humanized animals of Project 5.
New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this receptor
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