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.