Function of Neurexins

神经毒素的功能

• 批准号: 7986037
• 负责人: Thomas C. Sudhof
• 金额: $ 46.45万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986037
• 关键词: Accounting; Address; Affinity; Alternative Splicing; Autistic Disorder; Award; Binding; Biochemical; Biological; Biological Assay; Biophysics; Brain; Cell Adhesion Molecules; Cognition Disorders; Collaborations; Communication; Complex; Cues; Data; Disease; EGF-Like Domain; Electrophysiology (science); Employee Strikes; Exhibits; Exons; Figs - dietary; Functional disorder; GABA Receptor; Genes; Genetic; Hippocampus (Brain); Human Genetics; Impairment; Intercellular Junctions; Investigation; Laboratories; Learning; Left; Leucine-Rich Repeat; Ligand Binding; Ligands; Light; Measurement; Measures; Mediating; Membrane; Memory; Methods; Mus; Mutant Strains Mice; National Institute of Mental Health; Neurons; Pattern; Phenotype; Phosphotransferases; Physiological; Presynaptic Terminals; Property; Protein Chemistry; Protein Isoforms; Proteins; RNA Interference; RNA Splicing; Role; Schizophrenia; Shapes; Signal Transduction; Site; Slice; Specific qualifier value; Structure-Activity Relationship; Subfamily lentivirinae; Synapses; Synaptic Transmission; Synaptic Vesicles; Techniques; Tertiary Protein Structure; Testing; Wild Type Mouse; alpha-latrotoxin receptor; autism spectrum disorder; base; computerized data processing; dimer; esterase; in vivo; insight; interdisciplinary approach; mutant; neural circuit; novel; novel strategies; postsynaptic; presynaptic; public health relevance; receptor; research study; small hairpin RNA; synaptic function

DESCRIPTION (provided by applicant): Synapses are intercellular junctions that mediate neuronal communication, and likely involve many cell-adhesion molecules that connect pre- and postsynaptic neurons to each other. Neurexins are presynaptic cell-adhesion molecules that are essential for the formation of functional synapses, and for the specification of the properties of synapses. Neurexins are highly polymorphic due to extensive alternative splicing, interact with multiple postsynaptic cell-adhesion molecules, and are associated with autism-spectrum disorders and schizophrenia, which highlights their importance for synaptic circuits. However, how exactly neurexins function in synapses, and how this function is impaired in autism spectrum disorders and schizophrenia, remains unclear. In the present application, we propose four specific aims to examine how neurexins function in synapses. These aims utilize a combination of mouse genetics, electrophysiology, biophysics, and protein chemistry to determine the general functions of different neurexin isoforms, to understand the biological significance of their alternative splicing, to characterize how neurexins interact with multifarious ligands in a tightly regulated manner, and to elucidate the specific significance of their interactions with various ligands. These experiments will provide a comprehensive exploration of neurexin function and the mechanisms involved in this function, and clarify how neurexins act in specifying synapse properties. The results of these studies will not only provide insight into synaptic function in general, but also advance our understanding of synaptic dysfunction in cognitive disorders such as autism and schizophrenia. PUBLIC HEALTH RELEVANCE: Synapses mediate the communication between nerve cells in brain, and are impaired in cognitive diseases such as autism or schizophrenia. Synapses are formed by cell-adhesion molecules such as neurexins, which in recent studies have been implicated in schizophrenia and autism. In the present project, we will continue our long-term investigation of how neurexins function at synapses, and how impairments of their function leads to cognitive diseases. Results from this project will not only provide insight into how neurons communicate, but also promote our understanding of how such communication becomes dysfunctional in autism and schizophrenia.

描述（由申请人提供）：突触是介导神经元通信的细胞间连接，并且可能涉及许多连接前后突触神经元与彼此之间的细胞粘附分子。神经毒素是突触前细胞粘附分子，对于形成功能突触和突触的特性所必需。神经毒素由于广泛的替代剪接而具有高度多态性，与多个突触后细胞粘附分子相互作用，并且与自闭症 - 光谱疾病和精神分裂症有关，这突出了它们对突触电路的重要性。然而，神经毒素在突触中的确切功能以及自闭症谱系障碍和精神分裂症中该功能的损害如何损害。在本应用中，我们提出了四个特定的目的，以检查神经毒素如何在突触中的功能。这些目的利用小鼠遗传学，电生理学，生物物理学和蛋白质化学的组合来确定不同神经毒素同工型的一般功能，以了解其替代剪接的生物学意义，以表征神经毒素如何在紧密调节的方式中与多种互动的相互作用，并具有各种特定的相互作用。这些实验将对神经素功能和该功能所涉及的机制进行全面探索，并阐明神经毒素在指定突触特性中的作用。这些研究的结果不仅将提供一般的突触功能的见解，而且还可以提高我们对自闭症和精神分裂症等认知障碍中突触功能障碍的理解。 公共卫生相关性：突触介导大脑中神经细胞之间的交流，并在自闭症或精神分裂症等认知疾病中受到损害。突触是由细胞粘附分子（例如神经毒素）形成的，神经毒素在最近的研究中与精神分裂症和自闭症有关。在本项目中，我们将继续对神经毒素在突触中的功能以及其功能障碍的作用如何导致认知疾病的长期研究。该项目的结果不仅将提供有关神经元如何沟通的洞察力，而且还可以促进我们对自闭症和精神分裂症中这种沟通如何功能失调的理解。