Regulation of Memory Formation by the GTPase-activating Protein SynGAP

描述(申请者提供)：该项目重点研究通过学习激活并支持大脑中长期记忆形成的分子机制。许多信号通路位于NMDA受体(NMDAR)的下游，其中几条已被证明对记忆形成有重要贡献。这些信号事件被认为诱导了结构和功能上的突触改变。然而，人们对这些信号通路的调控知之甚少。我的实验室相信，理解学习过程中参与的空间和时间信号将为治疗记忆障碍的药物的开发产生强有力的目标。SynGAP与NMDAR相互作用，可以调节位于这些通道下游的广泛信号通路。这种蛋白质是独一无二的，因为它是PSD的核心成分，也能刺激小G蛋白的动态调节。有趣的是，SynGAP已被证明同时调节突触结构和功能，尽管介导SynGAP诱导的突触修改的信号通路尚不清楚。最近，在严重智力低下的儿童中发现了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的原因。我们假设SynGAP调控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位于学习激活的NMDAR下游，这将赋予该蛋白独特的能力，在突触处触发快速的结构和功能可塑性。这些突触变化将支持最终巩固新获得的记忆，这一假说可以解释SynGAP突变如何导致与智力低下相关的认知障碍。为了研究这一假说，我们建议使用一种新的方法来研究AMPAR运输和突触结构。我们将把SynGAP抑制肽与双光子成像和电生理学相结合，同时检测AMPAR功能的变化和突触结构的相应变化。然后，我们将尝试分离作为每种突触修饰基础的信号通路。最后，我们直接研究了SynGAP在海马区依赖记忆的获得、巩固和提取中的作用。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。总体而言，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，并可能导致潜在的记忆障碍和认知障碍的新治疗方法。 公共卫生相关性： 总体而言，这个项目探索了一个创新的假说，旨在评估和理解突触信号通路是否是中枢神经系统记忆形成机制的基础。了解学习所涉及的信号通路，如由SynGAP控制的信号通路，将使我们对蛋白质功能如何影响行为变化有新的见解，并有望为患有导致记忆功能障碍的疾病和条件的人带来新的治疗选择和药物开发途径。

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.