Inducible expression of mutant DISC1: transgenic mouse model

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DESCRIPTION (provided by applicant): The Disrupted-In-Schizophrenia-1 (DISC1) gene is an example of a strong candidate gene for studying the pathogenesis of schizophrenia. A balanced translocation that segregates in a large Scottish pedigree with schizophrenia and other major mental illnesses causes a deletion of the DISC1 gene, resulting in a truncated protein product that affects neurodevelopment. Genetic mouse models will advance our understanding of a role of mutant human DISC1 (hDISC1) in the pathogenesis of schizophrenia. In this exploratory application, we propose to characterize our new transgenic mouse model of inducible forebrain-restricted expression of mutant and full-length hDISC1 proteins. We will test the hypothesis that expression of mutant but not full-length hDISC1 affects mouse brain and behavior development. Specific Aim 1 will assess behavioral effects of mutant and full-length hDISC1 in developing and adult transgenic and control mice. We will use a standard battery of developmental tests to assess general mouse development, and various behavioral paradigms to evaluate sensory-motor gating, emotional responses, learning and memory and social behavior in mice. The proposed studies will identify key behavioral abnormalities in mutant hDISC1 transgenic mice. Specific Aim 2 will evaluate effects of mutant and full-length DISC1 on dendrite arbors of cortical and hippocampal pyramidal neurons and hippocampal granule cells in young and adult mice using the Golgi staining-based quantitative analysis. The proposed experiments will identify effects of mutant hDISC1 on the dendritic maturation in transgenic mice. Significance: The proposal will characterize developmental neurobehavioral effects of mutant hDISC1 and will facilitate future mechanistic studies of effects of the mutant DISC1 gene on neurodevelopment with relevance to the pathogenesis of schizophrenia and related mental disorders. The grant application proposes to characterize brain and behavior development in transgenic mice that bear a mutant human gene, Disrupted-In-Schizophrenia 1 (DISC1), which has been associated with schizophrenia and other major psychiatric disorders. The study will advance our understanding of effects of the mutant gene on brain maturation and behavioral abnormalities relevant to the pathogenesis of serious psychiatric diseases and will facilitate use of this new mouse model for pre-clinical therapeutic trials.