Mechanisms of synaptic plasticity and memory

描述(由申请人提供)：对肌动蛋白动态介导的突触强度和记忆形成变化背后的分子和细胞机制知之甚少。在这里，我们提出了一种假设，即调控哺乳动物雷帕霉素复合体2(MTORC2)是突触活性和涉及突触可塑性和记忆形成的肌动蛋白细胞骨架重构之间的联系。由于mTORC2是最近才发现的，人们对它的功能知之甚少，包括它是如何受到调节的，以及它在大脑中下游靶点的性质。这一建议结合了生化、转基因、药理学、电生理学、成像和行为学的方法来探索脑中mTORC2功能的几个关键方面，包括：a)它在突触可塑性和记忆中的作用，b)激活mTORC2的上游突触事件，以及c)mTORC2调节长期突触可塑性和长期记忆的下游分子机制。这项研究将深入了解学习和记忆背后的基本分子和细胞机制，可能导致与记忆功能障碍相关的疾病的新疗法，如衰老、发育和神经退行性疾病，这些疾病都会改变mTORC2的活性。 与公共健康相关：长期记忆的形成需要依赖于肌动蛋白聚合的大脑突触的结构变化。由于调控这些的关键信号通路尚不清楚，我们提出了一个多学科的方法来测试一个新的想法：最近发现的mTOR复合体2通过控制肌动蛋白细胞骨架的动力学来指导记忆的结构方面。这项研究将极大地促进我们对基本大脑过程的理解，并可能为治疗几种主要的认知障碍确定新的靶点，例如与年龄相关的记忆丧失，以及mTORC2活性改变的各种神经发育和神经退行性疾病。

DESCRIPTION (provided by applicant): Little is known about the molecular and cellular mechanisms underlying actin dynamic-mediated changes in synaptic strength and memory formation. Here we propose to test the hypothesis that the regulatory mammalian target of rapamycin complex 2 (mTORC2) is the link between synaptic activity and actin cytoskeleton restructuring involved in synaptic plasticity and memory formation. Since mTORC2 was only recently discovered, relatively little is known about its function, including how it is regulated ad the nature of its downstream targets in the brain. This proposal combines biochemical, transgenic, pharmacological, electrophysiological, imaging, and behavioral approaches to explore several crucial aspects of mTORC2 function in the brain including: a) its role in synaptic plasticity and memory, b) the up-stream synaptic events which activate mTORC2, and c) the downstream molecular mechanisms by which mTORC2 regulates long- term synaptic plasticity and long-term memory. This study will provide insight into the basic molecular and cellular mechanisms underlying learning and memory, possibly leading to new treatments for conditions associated with memory dysfunction such as aging, developmental and neurodegenerative disorders, all conditions in which mTORC2 activity is altered. PUBLIC HEALTH RELEVANCE: The formation of long-term memories requires structural changes at brain synapses that are dependent on actin polymerization. The key signaling pathways that regulate these being unknown, we propose a multidisciplinary approach to test a new idea: that the recently discovered mTOR complex 2 directs structural aspects of memory by controlling actin cytoskeleton dynamics. This study, will significantly advance our understanding of fundamental brain processes, and may identify new targets for the treatment of several major cognitive disorders such as age-related memory loss, and various neurodevelopmental and neurodegenerative disorders where mTORC2 activity is altered.