Control of long-term synaptic plasticity by neurexin ligands

中心PI：Malenka，Robert C.主要研究者（项目2）：Südhof，托马斯/Malenka，Robert 总结 虽然长时程突触可塑性已经研究了半个世纪，但其基本机制， 介导的过程，如NMDA受体依赖性LTP仍然在很大程度上是未知的，生物学 LTP的重要性尚未完全理解。在这里，我们提出了一个新的途径来理解LTP， 聚焦于我们最近意外的观察，两种不同的突触后细胞粘附分子， LRRTM和神经连接素都与突触前神经毒素结合，是正常LTP所必需的。本 该项目的指导假设是，了解跨突触信号介导的神经素为基础的 细胞粘附可以提供对协调的结构变化和囊泡运输事件的了解， 发生在LTP的突触后利用LRRTM的条件性敲除小鼠的四个具体目标和 神经配素被提出来检验这一总体假设。具体目标1将研究LRRTM和 神经连接素有助于LTP，特异性目标2将绘制LRRTM的候选分子相互作用， 神经连接素在LTP中的作用，具体目标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代内源性蛋白，特异性目标4将测试 LRRTM和神经连接素功能的行为意义，特别是在学习和记忆中， 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。在一起， 这些实验将促进我们对跨突触细胞粘附之间关系的理解 由neurexins及其配体和长期可塑性介导，从而不仅有助于了解如何 突触的形成和功能，但也涉及LTP如何诱导和表达。 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神经系统如何在神经系统中发挥作用， 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， 自闭症和精神分裂症，这些蛋白质与基因有关。 PHS 398/2590（Rev. 11/07）第1页

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