Translational Control in Synaptic Plasticity and Memory

描述（由申请人提供）：包括我的实验室在内的几个实验室已经证明，mTORC 1信号通路在啮齿动物的持久突触可塑性和长期记忆的蛋白质合成依赖性形式期间调节帽依赖性翻译。这些发现令人兴奋，因为它们首次证明了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，以获得更完整的理解突触可塑性和记忆过程中的翻译控制机制。首先，恐惧记忆再巩固所需的精确mTORC1依赖的翻译控制机制是什么？其次，恐惧消退学习和记忆所需的精确mTORC1依赖的翻译控制机制是什么？第三，在蛋白质合成依赖性突触可塑性过程中合成了哪些蛋白质，以及它们的合成需要哪些mTORC 1效应物？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，蛋白质印迹分析，免疫细胞化学，创新方法来测量新的蛋白质合成和识别新合成的蛋白质，以及新型基因修饰小鼠来研究突触可塑性，以及行为研究来研究mTORC1依赖性翻译在记忆功能中的作用。我们的实验结果将提供有关突触可塑性和多种形式记忆的信号机制的重要信息。最后，这些研究将产生关于突触可塑性改变的分子基础的关键信息 以及与mTORC1依赖性翻译失调相关的脑疾病中的行为。

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.