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

中心 PI：Malenka, Robert C. 首席研究员（项目 2）：Südhof, Thomas/Malenka, Robert 概括 尽管长期突触可塑性的研究已经有半个世纪了，但其基本机制 NMDA 受体依赖性 LTP 等介导过程仍然很大程度上未知，并且生物 LTP 的重要性尚不完全清楚。在这里，我们提出了一种理解 LTP 的新途径： 重点关注我们最近意想不到的观察结果，即两种不同的突触后细胞粘附分子， LRRTM 和神经连接蛋白均与突触前神经毒素结合，对于正常 LTP 至关重要。现在的 该项目以这样的假设为指导：了解基于神经毒素介导的跨突触信号传导 细胞粘附可以深入了解协调的结构变化和囊泡运输事件 LTP 期间发生突触后。利用 LRRTM 条件敲除小鼠的四个具体目标 提议使用神经肽来检验这一总体假设。具体目标 1 将研究 LRRTM 和 Neuroligins 有助于 LTP，具体目标 2 将绘制 LRRTM 和 LRRTM 的候选分子相互作用图 神经胶质素是其在 LTP 中发挥作用的基础，具体目标 3 将使用以下方法测试这些相互作用在 LTP 中的作用： 在条件敲除小鼠中用突变蛋白替换内源性蛋白，Specific Aim 4 将测试 LRRTM 和 Neuroligin 功能的行为意义，特别是在学习和记忆方面， 旨在开发 LTP 在记忆中的作用的测试，仅涉及 LTP 的高度选择性变化。一起， 这些实验将增进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介导和长期可塑性，因此不仅有助于深入了解如何 突触的形成和功能，还影响 LTP 的诱导和表达。 关联 在研究 LRRTM 和神经连接蛋白时，本项目不仅将阐明这些中枢神经元如何 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 这些蛋白质与自闭症和精神分裂症有遗传联系。 PHS 398/2590（修订版 11/07） 第 1 页 摘要