Project 3

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One of the recent excitements in the schizophrenia field is the identification of multiple susceptibility genes from human genetic association studies. Recent studies also reinforce the emerging view that schizophrenia is a disease of neuronal development in nature with an adult onset. How specific schizophrenia susceptibility genes regulate different aspects of neuronal development, however, is largely unknown. The hippocampus and hippocampal neurogenesis are stronly implicated in schizophrenia and depression, and in the therapeutic actions of many anti-depressants. Within the hippocampus, granule cells in the dentate gyrus are continuously generated from neural progenitors throughout life in all mammals examined, including humans. They follow stereotypic patterns of neuronal morphogenesis, migration, axon and dendritic targeting and become synaptic integrated into the exiting neuronal circuits within one month after birth. Such stereotypic and prolonged neuronal development of a single CMS neuronal subtype in a relative steady-state of mature CNS environment offers a unique opportunity to investigate molecular and cellular mechanisms of neuronal development in vivo. We have developed a retrovirus-mediated "single-cell genetic" approach for study of the development of newborn granule cells in the brain in vivo using a combinational approach of immunocytochemistry, multiphoton confocal microscopy, electron microscopy and electrophysiology. Using these approaches, we have recently examined the function of Disrupted-in-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, and shown that DISC1 regulates multiple phases of neuronal development of granule cells in vivo. In the current project, we aim to extent these preliminary findings and characterize the functions of DISC1 in conjunction with its interactors, such as NDEL1 and FEZ1, in regulating neurogenesis and neuronal development in vivo. We will also examine whether defects of neurogenesis from DISC1 dysfunction will lead to changes in animal behaviors. Furthermore, we will determine the molecular mechanisms underlying DISC1 in neurogenesis and neuronal development. We will also examine whether defects of neurogenesis from DISC1 dysfunction will lead to changes in animal behaviors. We envision our study will fill the gap of our basic knowledge about the functions of schizophrenia susceptibility genes in neuronal development and may reveal the etiology and pathogenesis of schizophrenia.