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：马伦卡，罗伯特C.首席研究员(项目2)：S，托马斯/马伦卡，罗伯特 摘要 尽管对长时突触可塑性的研究已有半个世纪的历史，但其基本机制 NMDA受体依赖的LTP等中介过程在很大程度上仍不清楚，生物学上 LTP的意义还没有完全被理解。在这里，我们提出了一种通过以下方式理解LTP的新方法 我们最近意外地观察到两种不同的突触后细胞黏附分子， LRRTM和神经连接蛋白都与突触前神经尿毒素结合，是正常LTP所必需的。现在 该项目的指导假设是，理解基于neuresin的跨突触信号传递 细胞黏附可以提供对协调的结构变化和囊泡运输事件的洞察 在LTP期间发生在突触后。利用LRRTMS和LRRTMS条件基因敲除小鼠的四个特定目标 神经连接素类被用来检验这一整体假说。具体目标1将检查LRRTM和 神经连接蛋白参与LTP，特异性目标2将绘制LRRTMS和LRRTM的候选分子相互作用图 神经连接蛋白在LTP中的作用，特异性目标3将测试这些相互作用在LTP中的作用 在条件性基因敲除小鼠中用突变蛋白替换内源性蛋白，以及特定的目标4将测试 LRRTM和神经连接蛋白功能的行为学意义，特别是在学习和记忆中 目的开发LTP在记忆中作用的测试，这些测试只涉及LTP的高度选择性变化。一起， 这些实验将促进我们对跨突触细胞黏附关系的理解。 由Neurexins及其配体和长期可塑性介导，从而不仅有助于洞察 突触的形成和功能，也与LTP的诱导和表达有关。 相关性 在研究LRRTM和神经连接蛋白时，本项目不仅将阐明这些中枢 突触的组织者有助于长期的可塑性和这种可塑性的机制，但也将 对这些蛋白质在神经精神障碍中的潜在作用有一个基本的了解 自闭症和精神分裂症，这些蛋白质与基因有关。 PHS 398/2590(11/07版)第1页摘要