Research Center for Molecular Pathogenesis of Schizophrenia

描述(申请人提供)：精神分裂症是一种神经元连接障碍，至少部分与发育性起源有关。大脑皮层功能障碍，特别是前额叶皮质的功能障碍，已被重复性报道。最近的遗传学研究表明，一些遗传易感因素可能在突触的形成中发挥作用。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和其他疾病易感因子，作为突触后密度的接头蛋白。因此，我们将研究DISC1参与的分子通路(S)在发育中的大脑皮层突触棘突形成中的作用。在这个项目的前半部分(目标1和2)，我们将使用原代皮质神经元来阐明DISC1/Kalirin-7和DISC1/nNOS/NDEL1在锥体神经元中正常形成脊椎的分子通路，可能是通过影响Rho样小G蛋白，特别是rac1。我们推测DISC1通过激活NMDA谷氨酸受体，调节Kalirin-7和NDEL1对rac1及其相关蛋白的访问，并以适当的方式调节突触棘突的形成。在这个项目的后半部分(目标3)，我们将测试DISC1的干扰及其与Kalirin-7和其他突触蛋白的相互作用如何导致体内脊柱的形态变化和导致行为变化，这将与Core B合作进行研究。本项目中研究的关键介质，包括Kalirin-7和rac1，将通过Core C的遗传分析进行评估。综上所述，我们希望阐明两个导致精神分裂症的关键因素，如谷氨酸和DISC1，如何在突触后部位发生聚合。我们希望阐明这种涉及DISC1及其相互作用的疾病途径导致额叶皮质锥体神经元突触棘突缺失和由此导致的行为异常的机制。

DESCRIPTION (provided by applicant): 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 two 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.