Project 1

精神分裂症是一种神经元连接障碍，至少部分是由发育引起的。功能性 大脑皮层，特别是前额叶皮质的功能障碍已被重现报道。近期 遗传学研究表明，一些遗传易感因素可能在形成过程中起作用。 突触的特征。这些因素包括精神分裂症(DISC1)、神经元型一氧化氮合酶 (NNOS)、Capon、NDEL1和ErbB4。DISC1与多种细胞内蛋白相互作用，包括Kalirin 等疾病的易感因素，作为突触后密度的接头蛋白。因此，我们 将研究分子通路(S)参与DISC1在突触形成中的作用 大脑皮层。在这个项目的前半部分(目标1和2)，我们将使用初级皮质神经元来 阐明DISC1/Kalirin-7和DISC1/nNOS/NDEL1在脊柱正常形成中的分子途径 锥体神经元，可能是通过影响Rho样小G蛋白，特别是rac1。我们假设 DISC1调节Kalirin-7和NDEL1对rac1和相关蛋白的访问，以响应激活 NMDA谷氨酸受体，并以适当的方式调节突触脊椎的形成。在第二个 这个项目的一半时间(目标3)，我们将测试DISC1的干扰以及它与Kalirin-7和其他 突触蛋白导致体内棘突的形态变化和行为改变， 将与Core B合作进行研究。本项目研究的主要介体包括Kalirin-7。 和rac1，将在Core C中通过遗传分析进行评估。总之，我们希望澄清 精神分裂症的两个关键因素，如谷氨酸和DISC1，在突触后汇聚 网站。我们希望阐明这一涉及DISC1及其相互作用的疾病途径的机制。 导致额叶皮质锥体神经元突触棘突的缺陷和由此产生的行为 异常现象。

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.