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

描述（由申请人提供）：中枢神经系统的整体结构和功能是通过各种精心策划的过程建立的，包括突触的形成和单个神经元树突状分支的形态发生。这些过程受到外部因素的影响，包括响应于诸如可卡因、安非他明、尼古丁和阿片类药物的施用而发生的神经元活动的变化。最近，小的GTdR Rem2被鉴定为兴奋性突触发育、树突棘形成和树突乔木形态的新调节剂。此外，Rem2介导树突状形态的能力依赖于Rem2与钙调蛋白（CaM）的结合。有趣的是，Rem2在转录水平上响应于神经元去极化而上调，这表明它可以充当直接连接，神经元可以通过根据需要改变其结构和功能来响应活性变化。 该提案旨在探索信号转导机制，通过该机制，Rem2介导树突状分支，以响应神经元活性的变化，在体外和体内。具体而言，体外培养的啮齿动物海马神经元系统将用于探索Rem2与CaM激酶II的相互作用，因为现有数据表明Rem2是这种已知的树突状形态调节剂的下游。为了探索Rem2在体内这种活动依赖性形态变化中的作用，非洲爪蟾蝌蚪的视顶盖，一个特征良好的实验系统，将被用来确定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在纹状体中表达，纹状体是与药物成瘾相关的奖励属性的作用部位，以及海马体，海马体已被证明在响应安非他明时发生结构变化。钙调素激酶信号的变化也被广泛地牵连在阿片类药物成瘾。因此，对Rem2参与的信号通路的全面研究将为大脑的基本结构如何改变以产生与药物使用和成瘾相关的功能变化提供新的见解。最终，Rem2可能是一个关键分子，外部刺激通过它介导对调节单个神经元和整个中枢神经系统结构的信号通路的直接影响。

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.