Function of Neurexins

尽管在了解突触如何工作方面已经取得了巨大的进展，但关于突触是如何形成的，以及突触的不同属性是如何被指定的，人们还知之甚少。最近的研究表明，neurexins在突触规范中起着核心作用，编码neurexins的基因突变导致自闭症和精神分裂症。Neurexins是突触前细胞黏附分子，对于正常的突触功能是必不可少的，它与多种突触后配体相互作用，这些配体反过来也与自闭症和精神分裂症有关，并以数千种选择性剪接、调节的亚型表达。本项目的总体目标是阐明neurexins作为模型生物在小鼠体内的基本细胞和电路功能，以便深入了解neurexins如何促进突触传递信息的能力，并促进对neurexins功能障碍如何易患神经精神疾病的理解。本项目提出了五个具体目标，即阐明neurexins介导的跨突触蛋白质相互作用网络(特异性目标1)，在单细胞水平上确定特定类型神经元中neurexins选择性剪接的经验依赖模式(特异性目标2)，阐明SS#4处neurexins选择性剪接的作用(特异性目标3)，利用CKO小鼠确定neurexins的相关功能(特异性目标4)，以及初步定义neurexin功能的机制。这些特定的目标将使用跨学科的方法组合来实现，这些方法主要包括小鼠遗传学、电生理学、基因表达研究、成像和蛋白质化学。这些特定的目的是相辅相成的，它们的结果将协同作用，产生一种对Neurexins的描述，将Neurexins与特定突触前和突触后配体的相互作用与其神经细胞类型特异性和活性依赖的表达、它们的选择性剪接以及它们的不同功能联系起来。通过这种方式，这个项目不仅将有助于我们对突触如何在神经回路中处理信息的基本理解，而且还将提供对Neuresin功能障碍如何导致神经精神障碍的洞察。

Although enormous progress has been achieved in understanding how synapses work, little is known about how synapses are formed, and how diverse synapse properties are specified. Recent work suggests that neurexins have a central role in synapse specification, and that mutations in genes encoding neurexins contribute to autism and schizophrenia. Neurexins are presynaptic cell-adhesion molecules that are essential for normal synapse function, interact with multiple of postsynaptic ligands which in turn have also been implicated in autism and schizophrenia, and are expressed in thousands of alternatively spliced, regulated isoforms. The overarching goal of the present project is to elucidate the basic cellular and circuit functions of neurexins in mice as a model organism in order to gain insight into how neurexins contribute to the ability of synapses to transmit information, and to promote the understanding of how impairments in neurexin functions predispose to neuropsychiatric disorders. The project proposes five specific aims, namely to elucidate the trans-synaptic protein interaction network mediated by neurexins (Specific Aim 1), to determine the experience-dependent patterns of neurexin alternative splicing in defined types of neurons at the single-cell level (Specific Aim 2), to elucidate the role of alternative splicing of neurexins at SS#4 (Specific Aim 3), to determine the relative functions of neurexins using cKO mice (Specific Aim 4), and to perform an initial definition of the mechanisms of neurexin function. These specific aims will be pursued using an interdisciplinary combination of methods that prominently include mouse genetics, electrophysiology, gene expression studies, imaging, and protein chemistry. The specific aims are complementary to each other, and their results will synergize in producing a description of neurexins that relates the interactions of neurexins with specific pre- and postsynaptic ligands to their neuronal cell type-specific and activity-dependent expression, their alternative splicing, and their diverse functions. In this manner, this project will not only contribute to our basic understanding of how synapses process information in neural circuits, but also provide insight into how neurexin dysfunction contributes to neuropsychiatric disorders.