Function of Neurexins

尽管在理解突触如何工作方面取得了巨大的进展，但对突触如何形成以及突触的不同特性是如何指定的知之甚少。最近的研究表明，神经毒素在突触规范中起着核心作用，编码神经毒素的基因突变导致了自闭症和精神分裂症。神经素是突触前细胞粘附分子，对正常突触功能至关重要，与多种突触后配体相互作用，而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、受调节的同种异构体表达。本项目的总体目标是阐明作为模型生物的小鼠神经xin素的基本细胞和电路功能，以便深入了解神经xin素如何促进突触传递信息的能力，并促进对神经xin素功能损伤如何易患神经精神疾病的理解。该项目提出了五个特定目标，即阐明由神经毒素介导的跨突触蛋白相互作用网络（specific Aim 1），确定单细胞水平上特定类型神经元中神经毒素选择性剪接的经验依赖模式（specific Aim 2），阐明神经毒素选择性剪接在SS#4中的作用（specific Aim 3），确定使用cKO小鼠的神经毒素的相对功能（specific Aim 4），并对神经素的功能机制进行初步定义。这些具体目标将采用跨学科的方法，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。具体目标是相互补充的，它们的结果将协同产生神经毒素的描述，将神经毒素与特定突触前和突触后配体的相互作用与神经元细胞类型特异性和活性依赖性表达，它们的替代剪接和它们的多种功能联系起来。通过这种方式，该项目不仅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，而且还有助于深入了解神经素功能障碍如何导致神经精神疾病。

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.