Project 1

精神分裂症是一种神经元连接障碍，至少部分是发育性的。功能 大脑皮层，特别是前额叶皮层的紊乱已经被反复报道。最近 遗传学研究表明，一些遗传易感性因素可能在形成 神经突触这些因子包括分裂型神经精神分裂症（DISC1）、神经元型一氧化氮合酶（NNOS）、神经元型一氧化氮合酶（NNOS）、神经元型一氧化氮合酶（NNOS）、神经元型一氧化氮合酶（NNOS）和神经元型一氧化氮合酶（NNOS）。 （nNOS）、CAPON、NDEL1和ErbB4。DISC 1与包括Kalirin在内的几种细胞内蛋白相互作用 以及其他疾病易感因素，作为突触后致密物中的衔接蛋白。因此我们 将研究分子通路的作用，涉及DISC1在突触棘形成在发展中国家， 大脑皮层在这个项目的前半部分（目标1和2），我们将使用初级皮层神经元， 阐明DISC1/Kalirin-7和DISC1/nNOS/NDEL1在正常脊柱形成中的分子途径 锥体神经元，可能通过影响Rho样小G蛋白，特别是Rac1。我们假设 DISC1调节Kalirin-7和NDEL1对Rac1和相关蛋白的接近，以响应活化 的NMDA谷氨酸受体，并以适当的方式调节突触棘的形成。在第二 本项目的一半（目标3），我们将测试DISC1的干扰及其与Kalirin-7和其他药物的相互作用， 突触蛋白导致体内棘的形态变化并导致行为改变， 将与核心B合作研究。该项目研究的关键介质，包括Kalirin-7 和Rac 1，将通过核心C中的遗传分析进行评价。综上所述，我们希望澄清 精神分裂症的关键因子，如谷氨酸和DISC1的会聚发生在突触后， 网站.我们希望阐明这种疾病途径的机制，包括DISC1及其相互作用因子， 导致额叶皮层锥体神经元突触棘的缺陷， 异常

Schizophrenia is a disorder of neuronal connectivity, at least in part, with developmental origin. Functional disturbance of the cerebral cortex, especially the prefrontal cortex, has been reproducibly reported. Recent genetic studies have suggested that some of the genetic susceptibility factors may have a role in formation of synapses. These factors include Disrupted-ln-Schizophrenia (DISC1), neuronal nitric oxide synthase (nNOS), CAPON, NDEL1, and ErbB4. DISC1 interacts with several intracellular proteins, including Kalirin and other susceptibility factors for the disease, as an adaptor protein in the postsynaptic density. Thus, we will study a role for molecular pathway(s) involving DISC1 in synaptic spine formation in the developing cerebral cortex. In the first half of this project (Aims 1 and 2), we will use primary cortical neurons to elucidate molecular pathways of DISC1/ Kalirin-7 and DISC1/nNOS/NDEL1 for proper spine formation in pyramidal neurons, possibly by influencing Rho-like small G-proteins, especially Rac1. We hypothesize that DISC1 regulates access of Kalirin-7 and NDEL1 to Rac1 and related proteins, in response to the activation of the NMDA glutamate receptor, and regulates synaptic spine formation in a proper manner. In the second half of this project (Aim 3), we will test how disturbance of DISC1 and its interaction with Kalirin-7 and other synaptic proteins lead to morphological changes of the spines in vivo and result in behavioral alterations, which will be studied in collaboration with Core B. Key mediators studied in this project, including Kalirin-7 and Rac1, will be evaluated by genetic analysis in Core C. Taken together, we hope to clarify how convergence of twto critical factors for schizophrenia, such as glutamate and DISC1, occurs at postsynaptic sites. We wish to elucidate mechanisms whereby this disease pathway, involving DISC1 and its interactors, leads to deficits in the synaptic spines in the pyramidal neurons of the frontal cortex and resultant behavioral abnormalities.