Regulation of Memory Formation by the GTPase-activating Protein SynGAP

描述（申请人提供）：本项目重点研究学习激活和支持大脑长期记忆形成的分子机制。许多信号通路位于NMDA受体（NMDARs）的下游，其中一些已被证明对记忆的形成有重要贡献。这些信号事件被认为可以诱导突触的结构和功能改变。然而，对这些信号通路的调控却知之甚少。我的实验室相信，理解在学习过程中参与的空间和时间信号，将为开发治疗记忆障碍的药物提供强有力的目标。SynGAP与NMDARs相互作用，可以调节这些通道下游的广泛信号通路。这种蛋白是独特的，因为它是PSD的核心成分，也刺激小g蛋白的动态调节。有趣的是，SynGAP已被证明可以调节突触结构和功能，尽管介导SynGAP诱导的突触修饰的信号通路尚不清楚。最近，在严重智力迟钝的儿童中发现了SynGAP的功能突变，这些突变被认为是导致这种疾病的非综合征和非遗传性形式。我们假设SynGAP调节树突棘中不同的信号通路，维持突触结构并限制AMPAR功能。我们认为SynGAP位于学习激活NMDARs的下游，这将赋予该蛋白独特的能力，以触发突触快速的结构和功能可塑性。这些突触的变化将支持新获得的记忆的最终巩固，这一假设可以解释SynGAP突变如何导致与智力迟钝相关的认知障碍。为了验证这一假设，我们提出了一种新的方法来研究AMPAR的转运和突触结构。我们将把SynGAP抑制肽与双光子成像和电生理学结合起来，同时检测AMPAR功能的变化和相应的突触结构的变化。然后，我们将尝试分离每种类型的突触修饰背后的信号通路。最后，我们直接研究了SynGAP在海马体依赖记忆的获取、巩固和检索中的作用。这种多方面的方法将在分子水平上解释调节信号动力学的突触蛋白（如SynGAP）如何支持动物新记忆的形成。总的来说，我们乐观地认为，这些研究将为学习和记忆的分子机制提供新的见解，并可能导致记忆障碍和认知障碍的潜在新治疗方法。

DESCRIPTION (provided by applicant): This project focuses on the molecular mechanisms that are activated by learning and support long-term memory formation in the brain. Many signaling pathways lie downstream of NMDA receptors (NMDARs), and several have been shown to contribute importantly to memory formation. These signaling events are believed to induce structural and functional synaptic modifications. However, the regulation of these signaling pathways is poorly understood. My laboratory believes that understanding the spatial and temporal signals that are engaged during the processes of learning will produce robust targets for the development of drugs that treat disorders of memory. SynGAP, which interacts with NMDARs, can regulate a broad spectrum of signaling pathways that lie downstream of these channels. This protein is unique because it is a core PSD component that also stimulates the dynamic regulation of small G-proteins. Interestingly, SynGAP has been shown to regulate both synapse structure and function, though the signaling pathways that mediate SynGAP-induced synaptic modifications are unknown. Recently, functional mutations in SynGAP were discovered in children with severe mental retardation, and these mutations are thought to cause non-syndromic and non-inherited forms of this disorder. We hypothesize that SynGAP modulates distinct signaling pathways in dendritic spines that maintains synapse structure and constrains AMPAR function. We believe that SynGAP lies downstream of learning-activated NMDARs, which would impart this protein with the unique ability to trigger rapid structural and functional plasticity at synapses. These synaptic changes would support the eventual consolidation of a newly acquired memory, and this hypothesis could explain how mutations in SynGAP cause cognitive impairments associated with mental retardation. To investigate this hypothesis, we propose to employ a novel approach to study AMPAR trafficking and synapse structure. We will combine SynGAP inhibitory peptides with two-photon imaging and electrophysiology to simultaneously assay changes in AMPAR function and corresponding changes to synapse structure. We will then attempt to dissociate signaling pathways that underlie each type of synaptic modification. Finally, we directly investigate the role of SynGAP in acquisition, consolidation and retrieval of hippocampus-dependent memories. This multifaceted approach will explain, at the molecular level, how a synaptic protein that regulates signaling dynamics, such as SynGAP, can support the formation of new memories in animals. Overall, we are optimistic that these studies will provide new insights into the molecular mechanisms of learning and memory, and could lead to potential new treatments for memory disorders and cognitive impairments. PUBLIC HEALTH RELEVANCE: Overall, this Project explores an innovative hypothesis aimed at evaluating and understanding if synaptic signaling pathways underlie the mechanisms of memory formation in the CNS. Understanding signaling pathways that are engaged by learning, such as those controlled by SynGAP, will give us novel insights into how protein function contributes to behavioral changes, and will hopefully lead to new treatment options and avenues for drug development for people with illnesses and conditions that cause memory dysfunction.