Mechanisms of synaptic plasticity and memory

描述（由申请人提供）：对于肌动蛋白动态介导的突触强度和记忆形成变化的分子和细胞机制知之甚少。在这里，我们建议检验以下假设：雷帕霉素复合物 2 (mTORC2) 的哺乳动物调节靶标是突触活动和参与突触可塑性和记忆形成的肌动蛋白细胞骨架重组之间的联系。由于 mTORC2 最近才被发现，人们对它的功能知之甚少，包括它的调节方式及其在大脑中下游靶标的性质。该提案结合了生物化学、转基因、药理学、电生理学、成像和行为方法，探索大脑中 mTORC2 功能的几个关键方面，包括：a）其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的基本分子和细胞机制，可能为与记忆功能障碍相关的疾病（如衰老、发育和神经退行性疾病，所有这些疾病中 mTORC2 活性发生改变）提供新的治疗方法。

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.