Translational Control in Synaptic Plasticity and Memory

描述(申请人提供)：包括我的实验室在内的几个实验室已经表明，在啮齿类动物依赖蛋白质合成的突触可塑性和长期记忆的形式中，mTORC1信号通路调节帽子依赖的翻译。这些发现引起了许多人的兴奋，因为他们首次证明了在突触可塑性和记忆过程中翻译的复杂生化调节。我们计划解决三个关键问题，以更全面地了解突触可塑性和记忆过程中的翻译控制机制。首先，恐惧记忆重新巩固所需要的依赖mTORC1的精确翻译控制机制是什么？第二，恐惧消退学习和记忆所需要的依赖mTORC1的精确翻译控制机制是什么？第三，在依赖蛋白质合成的突触可塑性过程中合成了哪些蛋白质，它们的合成需要哪些mTORC1效应器？这些可塑性诱导的蛋白质在记忆形成过程中也会上调吗？这些问题将通过利用电生理记录、Western印迹分析、免疫细胞化学、测量新蛋白质合成和识别新合成蛋白质的创新方法、研究突触可塑性的新型转基因小鼠以及检查mTORC1依赖翻译在记忆功能中的作用的行为研究的强大多学科组合来解决。我们的实验结果将提供有关突触可塑性和多种形式记忆背后的信号机制的重要信息。最后，这些研究将产生有关突触可塑性改变的分子基础的关键信息 以及与调节失调的mTORC1依赖的翻译相关的大脑障碍的行为。

DESCRIPTION (provided by applicant): Several laboratories, including my laboratory, have shown that the mTORC1 signaling pathway regulates cap-dependent translation during protein synthesis-dependent forms of long-lasting synaptic plasticity and long-term memory in rodents. These findings have generated much excitement because they were the first demonstration of the complex biochemical regulation of translation during synaptic plasticity and memory. We plan to address three critical questions to gain a more complete understanding of the translational control mechanisms operating during synaptic plasticity and memory. First, what are the precise mTORC1-dependent translational control mechanisms that are required for fear memory reconsolidation? Second, what are the precise mTORC1-dependent translational control mechanisms that are required for fear extinction learning and memory? Third, what proteins are synthesized during protein synthesis-dependent synaptic plasticity and which mTORC1 effectors are required for their synthesis? Are these plasticity-induced proteins also upregulated during memory formation? These questions will be addressed by utilizing the powerful multidisciplinary combination of electrophysiological recordings, Western blot analyses, immunocytochemistry, innovative methods to measure new protein synthesis and identify newly synthesized proteins, and novel genetically-modified mice to study synaptic plasticity, as well as behavioral studies to examine the role of mTORC1-dependent translation in memory function. The results of our experiments will provide important information concerning the signaling mechanisms that underlie synaptic plasticity and multiple forms of memory. Finally, these studies will generate critical information about the molecular basis of altered synaptic plasticity and behavior in brain disorders associated with dysregulated mTORC1-dependent translation.