Control of long-term synaptic plasticity by neurexin ligands

神经毒素配体控制长期突触可塑性

• 批准号: 8854549
• 负责人: Thomas C. Sudhof
• 金额: $ 35.57万
• 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: 2015-04-15 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8854549
• 关键词: AMPA Receptors; Actins; Address; Alternative Splicing; Applications Grants; Autistic Disorder; Behavioral; Behavioral Mechanisms; Binding; Binding Proteins; Biochemical; Biological; Cell Adhesion; Cell Adhesion Molecules; Cells; Competence; Development; Disease; Ensure; Event; Goals; Hippocampus (Brain); Injection of therapeutic agent; Knockout Mice; Learning; Life; Ligands; Light; Link; Maps; Measurement; Mediating; Memory; Molecular; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Physiological; Principal Investigator; Probability; Process; Property; Proteins; Role; Schizophrenia; Signal Pathway; Signal Transduction; Specificity; Synapses; Synaptic plasticity; Testing; Time; Vertebral column; Virus; base; behavior test; behavioral study; cell type; chemical function; hippocampal pyramidal neuron; implicit memory; insight; interdisciplinary approach; mutant; neural circuit; neuropsychiatry; novel; postsynaptic; presynaptic; recombinase; research study; synaptic function; tool; trafficking

Center PI: Malenka, Robert C. Principal Investigator (Project 2): Südhof, Thomas/Malenka, Robert Summary Although long-term synaptic plasticity has been studied for half a century, the fundamental mechanisms that mediate process such as NMDA-receptor-dependent LTP remain largely unknown, and the biological significance of LTP is incompletely understood. Here, we propose a novel avenue to understanding LTP by focusing on our recent unexpected observation that two different postsynaptic cell-adhesion molecules, LRRTMs and neuroligins which both bind to presynaptic neurexins, are essential for normal LTP. The present project is guided by the hypothesis that understanding trans-synaptic signaling mediated by neurexin-based cell adhesion may provide insight into the coordinated structural changes and vesicular trafficking events that occur postsynaptically during LTP. Four specific aims utilizing conditional knockout mice of LRRTMs and neuroligins are proposed to test this overall hypothesis. Specific Aim 1 will examine how LRRTMs and neuroligins contribute to LTP, Specific Aim 2 will map candidate molecular interactions of LRRTMs and neuroligins that underlie their function in LTP, Specific Aim 3 will test the role of these interactions in LTP using replacement of endogenous with mutant proteins in conditional knockout mice, and Specific Aim 4 will test the behavioral significance of the function of LRRTMs and neuroligins especially in learning and memory, with the aim to develop tests of the role of LTP in memory that involve highly selective changes in only LTP. Together, these experiments will advance our understanding of the relation between trans-synaptic cell adhesion mediated by neurexins and their ligands and long-term plasticity, thus contributing not only insight into how synapses are formed and function, but also into how LTP is induced and expressed. Relevance In studying LRRTMs and neuroligins, the present project will not only shed light on how these central organizers of synapses contribute to long-term plasticity and on the mechanisms of such plasticity, but will also provide a basic understanding of the potential role of these proteins in neuropsychiatric disorders such as autism and schizophrenia to which these proteins have been linked genetically. PHS 398/2590 (Rev. 11/07) Page 1 Summary

PI中心：Malenka，Robert C.首席研究员（项目2）：Südhof，Thomas/Malenka，Robert 概括 尽管长期的突触可塑性已经研究了半个世纪，但基本机制 诸如NMDA受体依赖性LTP之类的介导过程仍然未知，并且生物学 LTP的意义不完全理解。在这里，我们提出了一条新颖的途径来了解LTP 关注我们最近的意外观察，即两个不同的突触后细胞粘附分子， LRRTM和神经素都与突触前神经氧素结合，对于正常LTP至关重要。现在 项目的指导是：理解基于神经毒素介导的跨突触信号传导 细胞粘附可能会深入了解协调的结构变化和囊泡贩运事件，这些事件 LTP期间发生突触后发生。使用有条件的LRRTM和有条件敲除小鼠的特定目的 提出了神经素来检验这一总体假设。具体目标1将检查LRRTM和 神经素有助于LTP，具体AIM 2将绘制LRRTMS的候选分子相互作用和 神经素是其在LTP中功能的基础的神经素，具体AIM 3将使用LTP中这些相互作用的作用 用条件敲除小鼠中的突变蛋白代替内源性，具体的目标4将测试 LRRTM和神经素功能功能的行为意义，尤其是在学习和记忆方面 旨在制定LTP在仅LTP中高度选择性变化的内存中的作用的测试。一起， 这些实验将提高我们对跨突触细胞粘附之间关系的理解 由神经毒素及其配体和长期可塑性介导，因此不仅有助于了解如何 突触形成并发挥功能，也可以进入LTP的诱导和表达方式。 关联 在研究LRRTM和神经素时，本项目不仅会阐明这些中心 突触的组织者有助于长期可塑性和这种可塑性的机制，但也将 提供对这些蛋白质在神经精神疾病中的潜在作用的基本了解，例如 这些蛋白质已与之相关的自闭症和精神分裂症。 PHS 398/2590（Rev. 11/07）第1页摘要