Function of Neurexins

神经毒素的功能

• 批准号: 8932978
• 负责人: Thomas C. Sudhof
• 金额: $ 71.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932978
• 关键词: Address; Affinity; Alternative Splicing; Animal Model; Autistic Disorder; Biochemical; Brain; Cell Adhesion Molecules; Cells; Code; Communication; Disease; Electrophysiology (science); Functional disorder; Funding; Gene Expression; Generations; Genes; Genetic; Goals; Human Genetics; Image; Impairment; Instruction; Investments; Ligands; Link; Maps; Mediating; Messenger RNA; Methods; Mus; Mutate; Mutation; Neurons; Pattern; Period Analysis; Phenotype; Plastics; Process; Progress Reports; Property; Protein Chemistry; Protein Isoforms; Proteins; RNA Splicing; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; Schizophrenia; Site; Specific qualifier value; Synapses; Synaptic Transmission; Technology; Testing; Time; Work; behavioral study; cell type; experience; gene function; genetic analysis; information processing; insight; mutant; neural circuit; neuropsychiatry; novel; postsynaptic; presynaptic; protein protein interaction; research study; synaptic function; synaptogenesis

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. RELEVANCE (See instructions): Major recent progress revealed that the presynaptic cell-adhesion molecules neurexins and their ligands are genetically linked to autism, schizophrenia, and other neuropsychiatric disorders, but the basic functions of these molecules and the consequences of their dysfunction are incompletely understood. In addressing these issues, the present project will illuminate the pathogenic mechanisms underlying these disorders.

虽然在了解突触如何工作方面已经取得了巨大的进展，但对突触如何形成以及突触的不同属性如何指定却知之甚少。最近的研究表明，neurexins在突触特化中起着核心作用，并且编码neurexins的基因突变有助于自闭症和精神分裂症。神经毒素是正常突触功能所必需的突触前细胞粘附分子，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，并且以数千种可变剪接的调节亚型表达。本项目的总体目标是阐明神经毒素在小鼠中作为模式生物的基本细胞和电路功能，以深入了解神经毒素如何促进突触传递信息的能力，并促进对神经毒素功能障碍如何易患神经精神疾病的理解。该项目提出了五个具体目标，即阐明神经毒素介导的跨突触蛋白质相互作用网络（具体目标1），在单细胞水平确定确定神经元中neurexin选择性剪接的经验依赖性模式（具体目标2），阐明神经毒素在SS#4的可变剪接的作用（具体目标3），使用cKO小鼠确定neurexins的相关功能（具体目标4），并对neurexin功能的机制进行初步定义。这些具体的目标将采用跨学科的方法，主要包括小鼠遗传学，电生理学，基因表达研究，成像和蛋白质化学的组合来追求。具体的目标是相互补充，他们的结果将协同产生的neurexins的描述，涉及到神经毒素与特定的前和突触后配体的相互作用，其神经元细胞类型特异性和活性依赖性表达，其选择性剪接，以及其不同的功能。以这种方式，这个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， 深入了解neurexin功能障碍如何导致神经精神疾病。 相关性（参见说明）： 最近的主要进展表明，突触前细胞粘附分子neurexins及其配体与自闭症，精神分裂症和其他神经精神疾病有遗传联系，但这些分子的基本功能及其功能障碍的后果还不完全清楚。在解决这些问题，本项目将阐明这些疾病的致病机制。