Functions of DISC1 and APP in Cortical Development and Neuropsychiatric Disorders

皮质细胞迁移的缺陷与一系列表型有关，包括癫痫、精神分裂症、癫痫、精神分裂症、精神 发育迟缓、自闭症和精神分裂症（SZ）。在过去，人类基因的功能分析与 经典的神经元迁移障碍已经对迁移途径产生了有价值的见解 以及这些疾病的根本原因。对啮齿动物的研究为这一清单增加了额外的因素， 迁移所需的基因。其中一个因素是淀粉样前体蛋白（APP），一种阿尔茨海默病 连锁基因，这是所需的正常迁移到皮层板和神经元的过程 结果此外，有几个基因与精神分裂症有关，如D1 SC 1、PDE 4和NRG 1， 所有这些都在神经元发育，包括迁移和神经突生长中起重要作用。最近 研究将涉及AP 0 ER 2、DAB 1和LIS 1等因子的经典迁移途径与APP 和某些SZ连锁基因该提案旨在1）将这些新确定的参与者纳入 已建立的迁移和神经突生长途径; 2）阐明某些突变和变异是如何在 SZ相关基因导致迁移缺陷;以及3）解决迁移缺陷和/或细微缺陷是否导致迁移缺陷。 神经元突起生长的改变导致神经递质及其受体水平的改变， 在SZ患者中有描述。子宫内电穿孔的体内方法将用于 表达编码候选蛋白的野生型或突变形式的shRNA或cDNA，以评估 它们的表达改变对胚胎大鼠脑中神经元前体迁移的影响。 还将利用原代神经元培养物来分析这些不同构建体对神经元的影响。 过程副产物。最后，神经递质受体表达（使用生物化学和 免疫组织化学）和神经递质水平（使用微透析和HPLC）将在 啮齿类动物，不同的基因操作导致了不同程度的皮质紊乱， 迁移这组实验将解决神经元迁移异常是神经元迁移异常的假设。 与SZ患者中观察到的神经递质系统缺陷有关。

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 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 D1SC1, 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 AP0ER2, DAB1, and LIS1 with both APP and certain SZ-linked genes. This proposal 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 neuonal 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.