The Role of the Activity-Regulated GTPase Rem2 in Dendrite Development

描述(申请人提供)：中枢神经系统的整体结构和功能是通过各种精心编排的过程建立的，包括突触的形成和单个神经元树突树枝的形态发生。这些过程受到外部因素的影响，包括对可卡因、安非他明、尼古丁和鸦片类药物的服药引起的神经元活动的变化。最近，小GTP酶Rem2被发现是兴奋性突触发育、树突棘形成和树突分枝形态的一个新的调节因子。此外，Rem2调节树突形态的能力依赖于Rem2与钙调蛋白(CaM)的结合。有趣的是，Rem2在转录水平上上调是对神经元去极化的反应，这表明它可以作为一个直接链接，通过它可以根据需要改变其结构和功能，从而对活动的变化做出反应。这一建议试图探索Rem2介导树突树枝形成的信号机制，以响应体外和体内神经元活动的变化。具体地说，一个体外培养的啮齿动物海马神经元系统将被用来探索Rem2与CaM激酶II的相互作用，因为现有的数据表明，Rem2位于这一已知的树突形态调节因子的下游。为了探索Rem2在活体内这种依赖活动的形态变化中的作用，我们将利用非洲爪哇蝌蚪的视顶盖这一具有良好特性的实验系统，来确定Rem2如何以视觉感觉体验的形式参与活动引起的形态变化。重要的是，Rem2在纹状体和海马体中表达，纹状体是与药物成瘾相关的奖赏属性的作用部位，海马体已被证明对苯丙胺的反应经历了结构变化。CaM激酶信号的变化也被广泛地与阿片成瘾有关。因此，对Rem2参与的信号通路的全面研究将为我们提供新的见解，了解大脑的潜在结构是如何改变的，从而产生与药物使用和成瘾相关的功能变化。最终，Rem2可能代表着一个关键分子，外部刺激通过该分子直接影响那些调节单个神经元和整个中枢神经系统结构的信号通路。 与公共卫生相关：个体神经元和神经元网络的潜在结构受到仔细的监管，以确保中枢神经系统(CNS)的正常功能。然而，随着滥用药物的管理，中枢神经系统结构的许多方面都发生了变化。我希望探索Rem2的信号通路，这是一种参与这些相同过程的新蛋白质，以提供对慢性药物滥用改变神经元结构的机制的新见解。)

DESCRIPTION (provided by applicant): The overall structure and function of the central nervous system is established via a variety of carefully orchestrated processes, including the formation of synapses and the morphogenesis of the dendritic arborization of individual neurons. These processes are subject to influence by external factors, including the changes in neuronal activity that occur in response to the administration of drugs such as cocaine, amphetamines, nicotine, and opiates. Recently, the small GTPase Rem2 was identified as a novel regulator of excitatory synapse development, dendritic spine formation, and dendritic arbor morphology. Additionally, the ability of Rem2 to mediate dendritic morphology is dependent on Rem2 binding to calmodulin (CaM). Interestingly, Rem2 is upregulated at the transcriptional level in response to neuronal depolarization, suggesting that it can act as a direc link by which a neuron can respond to changes in activity by altering its structure and function as needed. This proposal seeks to explore the signaling mechanisms through which Rem2 mediates dendritic arborization in response to changes in neuronal activity both in vitro and in vivo. Specifically, an in vitro system of cultured rodent hippocampal neurons will be used to explore the interaction of Rem2 with CaM kinase II, as existing data suggests that Rem2 is downstream of this known regulator of dendritic morphology. To explore the role of Rem2 in such activity-dependent changes in morphology in vivo, the optic tectum of Xenopus laevis tadpoles, a well-characterized experimental system, will be used to identify how Rem2 participates in the morphological changes caused by activity in the form of visual sensory experience. Importantly, Rem2 is expressed in the striatum, which is the site of action of the reward attributes associated with drug addiction, as well as the hippocampus, which has been shown to undergo structural changes in response to amphetamines. Changes in CaM kinase signaling have also been extensively implicated in opiate addiction. Thus, a comprehensive study of the signaling pathways in which Rem2 is involved will provide new insights into how the underlying structure of the brain is altered to produce the functional changes associated with drug use and addiction. Ultimately, Rem2 may represent a key molecule through which external stimuli mediate direct effects on those signaling pathways that regulate the structure of individual neurons and the central nervous system as a whole. PUBLIC HEALTH RELEVANCE: The underlying structure of individual neurons and neuronal networks is carefully regulated to ensure the proper functioning of the central nervous system (CNS). However, many aspects of CNS structure are altered following the administration of drugs of abuse. I wish to explore the signaling pathways of Rem2, a novel protein that has been implicated in these same processes, to provide new insight into the mechanisms by which chronic drug abuse acts to change the structure of neurons. )