Functions of DISC1 and APP in Cortical Development and Neuropsychiatric Disorders

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DESCRIPTION (provided by applicant): Defects of cortical cell migration have been linked to a spectrum of phenotypes that include epilepsy, mental retardation, autism, and schizophrenia (SZ). In the past, functional analyses of human genes linked to classic disorders of neuronal migration such as lissencephaly have yielded valuable insights into the pathways involved in migration and the underlying causes of these diseases. Studies in rodents have added additional factors to the list of genes necessary for migration. One such factor is Amyloid Precursor Protein (APP), an Alzheimer's Disease linked gene, which is required for both normal migration into the cortical plate and neuronal process outgrowth. In addition, several genes have been linked to schizophrenia such as DISC1, PDE4, and NRG1, all of which play important roles in neuronal development, including migration and neurite outgrowth. Recent studies link classic pathways of migration involving factors such as APOER2, DAB1, and LIS1 with both APP and certain SZ-linked genes. This application aims to 1) integrate these newly identified players into established migration and neurite outgrowth pathways; 2) elucidate how certain mutations and variants in SZ-associated genes lead to defects in migration; and 3) address whether defects in migration and/or subtle alterations in neuronal process outgrowth lead to altered levels of neurotransmitters and their receptors, both of which are described in patients with SZ. The in vivo method of in utero electroporation will be used to express shRNAs or cDNAs encoding wild type or mutated versions of candidate proteins to assess the effects of their altered expression on neuronal precursor migration in the context of the embryonic rat brain. Primary neuronal cultures also will be utilized to analyze the effects of these various constructs on neuronal process outgrowth. Lastly, both neurotransmitter receptor expression (using biochemistry and immunohistochemistry) and neurotransmitter levels (using microdialysis and HPLC) will be analyzed in rodents in which different genetic manipulations have caused varying degrees of disordered cortical migration. This set of experiments will address the hypothesis that abnormalities in neuronal migration are linked to defects in the neurotransmitter systems that are observed in patients with SZ.