Regulation of growth and pruning of neuronal arbors

描述(申请人提供)：本项目研究调节中枢神经系统神经元树突形态的分子机制。树突分支的结构决定了突触回路的连接和突触输入的整合。因此，对神经元形态的控制和动态调节对神经系统的正常功能至关重要。该项目专注于一种名为α-嵌合体的基因，该基因可能是神经元形态发生的重要调节因子。两种α-嵌合体在发育中的神经系统中表达，其功能是作为Rho-GTP酶的GTP酶激活蛋白。本研究的目的是了解α-嵌合体在小鼠神经丛的形成和可塑性中的作用和调节。该项目结合了生化、细胞生物学和解剖学方法来研究这些蛋白质在海马神经元和小脑神经元中的功能。拟议的实验将首先研究α-嵌合体功能在调节树枝形态中的分子机制(目标1)。随后，我们将研究α-嵌合体是如何受突触活动调节的(目标2)。最后，我们将培育缺乏单个或多个α-嵌合蛋白亚型的突变小鼠，并分析体内树突和轴突的发育(目标3)。这些研究将探索一种将神经元信号与Rho-GTP酶对细胞形态的动态调节联系起来的分子机制。这些机制可能与神经系统的正常发育有关，也与成年生物体中神经元连接的可塑性有关。药物滥用后，可观察到树突结构的改变。α-嵌合体是与这种变化相关的很好的候选因素，因为它们在功能上与与成瘾有关的信号通路耦合。此外，α-嵌合体的缺陷被认为与自闭症和精神分裂症有关。因此，了解α-嵌合体的细胞功能与人类健康密切相关。

DESCRIPTION (provided by applicant): 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.