Mechanisms of Synapse Remodeling

突触重塑是形成和消除突触以重组现有大脑的过程 神经回路，对于建立和维持神经系统的完整性是不可或缺的。突触 在动物的一生中不断重塑。青少年神经症的重塑高峰 系统，在整个成年期保持平稳，并随着衰老而下降。我研究的长期目标是 确定介导突触重塑的信号通路和分子机制。这会有帮助的 我们要了解突触是如何在正确的时间和正确的地点形成和消除的，并提供 了解和治疗无数神经病的终极目标的基本信息 疾病和精神障碍。为了在分子水平上探讨突触重塑的分析， 从一个简单的无脊椎动物模型开始，信息丰富。在线虫中，突触重塑发生在可靠的 在发展过程中以可预测的方式。在第一幼虫阶段结束时，6个运动神经元反转 它们的轴突-树突极性，分解现有的突触，并在遥远的位置形成新的突触。这 简单的重新布线过程提供了一个极好的模型系统，这两个分子都可以访问 手法和活体光学观察。我提议的研究的目的是调查 决定突触重塑时间的分子通路和识别参与突触重塑的新基因 切换突触的身份。这一建议包括以下目的：第一，我将调查 突触重构的时间调节，测试负责控制突触重构的基因的假说 发育事件序列(异时基因)调节突触重构。第二，我会 结合来自微阵列分析、RNAi筛查和ForWord基因筛查的数据来确定新的因素 是突触重塑所必需的。最后，将使用一种新的定量成像分析方法来 确定介导突触降解的泛素-蛋白酶体系统的空间调节 突触重塑过程中的成分。总之，本提案中概述的实验将提供一种 突触重塑及其调控的机制认识。

Synapse remodeling is the process of forming and eliminating synapses to reorganize the existing brain circuitry, and is indispensable for establishing and maintaining the integrity of the nervous system. Synapses are constantly remodeled throughout the lifetime of an animal. Remodeling peaks in the juvenile nervous system, levels off throughout adulthood, and declines with senescence. The long-term goal of my research is to identify the signaling pathways and molecular machinery that mediate synapse remodeling. This will help us to understand how synapses are formed and eliminated at the right time and right place, and provide fundamental information towards our ultimate goal of understanding and treating numerous neurological diseases and mental disorders. To approach analysis of synapse remodeling at the molecular level, it is informative to begin with a simple invertebrate model. In C. elegans, synapse remodeling occurs in a reliable and predictable manner during development. At the end of the first larval stage, 6 motor neurons reverse their axon-dendrite polarity, disassemble existing synapses, and form new ones in a distant location. This simple rewiring process provides an excellent model system that is accessible to both molecular manipulation and in vivo optical observation. The objective of my proposed research is to investigate the molecular pathways defining the timing of synapse remodeling and to identify new genes involved in switching the identity ofthe synapses. This proposal includes the following aims: first, I will investigate temporal regulation of synapse remodeling, testing the hypothesis that genes responsible for controlling the sequence of developmental events (heterochronic genes) regulate synapse remodeling. Second, I will combine data from microarray analysis, a RNAi screen and a forword genetic screen to identify new factors required for synapse remodeling. Finally, a novel quantitative imaging analysis approach will be used to determine spatial regulation ofthe ubiquitin-proteasome system mediating degradation of synaptic components during synapse remodeling. Together, the experiments outlined in this proposal will provide a mechanistic understanding of synapse remodeling and its regulation.