Regulation of growth and pruning of neuronal arbors

该项目研究了调节神经元树突形态的分子机制， 中枢神经系统树突分支的结构决定了突触回路的布线 以及突触输入的整合。因此，神经元形态的控制和动态调节是 对正常的神经系统功能至关重要 该项目的重点是一个名为α-chimaerin的基因，它可能是一个重要的调节因子， 神经元形态发生两种α-嵌合蛋白亚型在发育中的神经系统中表达， 作为Rho-GTP酶的GTP酶激活蛋白发挥功能。本提案的目的是了解 α-嵌合蛋白在小鼠神经元乔木形成和可塑性中的功能和调节。的 该项目采用生物化学、细胞生物学和解剖学方法相结合的方法来研究 这些蛋白质在海马和小脑神经元中的功能。这些实验将首先 研究a-嵌合蛋白调节树突状乔木形态的分子机制 (Aim 1）。随后，我们将研究α-嵌合蛋白是如何调节突触活动（目的2）。最后， 我们将产生缺乏单个或多个α-嵌合蛋白同种型的突变小鼠，并分析其基因突变。 体内树突和轴突的发育（Aim 3）。 这些研究将探讨一种分子机制，这种机制将神经元信号传导与动态 Rho-GTP酶对细胞形态的调节。这些机制可能与正常情况有关， 神经系统的发育，但也为可塑性的神经元连接在成年有机体。 在药物滥用后观察到树突的结构改变。阿尔法嵌合体是很好的候选者 与这些变化相关的因素，因为它们在功能上与涉及的信号通路偶联。 上瘾此外，已经提出α-嵌合蛋白的缺陷与自闭症相关， 精神分裂症因此，了解α-嵌合蛋白的细胞功能对于人类的健康是高度相关的。 健康

This project investigates the molecular mechanisms that regulate the dendritic morphology of neurons in the central nervous system. The architecture of dendritic arborizations determines the wiring of synaptic circuits and the integration of synaptic inputs. Therefore, control and dynamic regulation of neuronal morphology are crucial for normal nervous system function. This project focuses on one gene named alpha-chimaerin that is likely to be an important regulator of neuronal morphogenesis. Two a-chimaerin isoforms are expressed in the developing nervous system that function as GTPase activating proteins for Rho-GTPases. It is the goal of this proposal to understand the function and regulation of a-chimaerins in the formation and plasticity of neuronal arbors in mice. The project employs a combination of biochemical, cell biological, and anatomical approaches to investigate the function of these proteins in hippocampal and cerebellar neurons. The proposed experiments will first examine the molecular mechanism of a-chimaerin function in regulating the morphology of dendritic arbors (Aim 1). Subsequently, we will investigate how a-chimaerin is regulated by synaptic activity (Aim 2). Finally, we will generate mutant mice lacking individual or multiple a-chimaerin isoforms and analyze the development of dendritic and axonal arbors in vivo (Aim 3). These studies will investigate a molecular mechanism that links neuronal signaling with the dynamic regulation of cell morphology by Rho-GTPases. These mechanisms are likely to be relevant for the normal development of the nervous system but also for the plasticity of neuronal connections in the adult organism. Structural alterations in dendrites are observed after drug abuse. Alpha-chimaerins are good candidate factors to be relevant for such changes since they are functionally coupled to signaling pathways implicated in addiction. Moreover, defects in a-chimaerins have been proposed to be associated with autism and schizophrenia. Understanding the cellular functions of a-chimaerins is therefore highly relevant for human health.