Translational Control in Long-Term Synaptic Plasticity

描述（由申请人提供）：神经生物学的一个中心问题涉及突触功能和结构持久改变的分子机制。深入了解这些机制将对人类认知和神经精神疾病具有广泛的相关性。突触可塑性和记忆的持久形式需要新的蛋白质合成，但对潜在的调控机制知之甚少。ERK/MAPK和mTOR信号通路与突触可塑性有关，但它们对长期突触可塑性和记忆的蛋白质合成依赖性过程的可能贡献尚未得到研究。在本申请中，显性阴性形式的MEK 1在出生后鼠前脑中的条件性表达显示出抑制ERK活化并导致海马记忆巩固和海马LLTP的翻译依赖性、转录非依赖性阶段的选择性缺陷。在海马神经元中的翻译研究表明，ERK抑制阻断神经元活性诱导的蛋白质合成的方式独立于顺式作用的mRNA序列。这些结果表明，ERK信号传导在突触可塑性和记忆的持久形式中对翻译控制起着至关重要的作用。为了扩展这些发现，将测试以下假设：1）ERK和mTOR通路通过翻译机器的关键组分的磷酸化来调节响应神经元活动的蛋白质合成; 2）ERK依赖的翻译诱导对于蛋白质合成依赖的双向突触可塑性（即L-LTP和L LTD）的建立是必需的; 3）ERK依赖的翻译调控在树突棘的结构可塑性中起重要作用。职业发展计划将通过与麻省理工学院的两名资深调查员Mark Bear和Morgan Sheng的合作以及在当地研讨会和国际会议上出席和展示结果来加强。记忆障碍的临床工作将补充拟议的研究。MGH神经科为拟议的职业发展计划提供了丰富多样的科学环境，这将有助于建立一个致力于了解人类认知和认知障碍机制的研究计划。

DESCRIPTION (provided by applicant): A central problem in neurobiology concerns the molecular mechanisms underlying enduring modifications of synaptic function and structure. Insights into these mechanisms will have broad relevance to human cognition and neuropsychiatric disease. Enduring forms of synaptic plasticity and memory require new protein synthesis, but little is known about the underlying regulatory mechanisms. The ERK/MAPK and mTOR signaling pathways have been implicated in synaptic plasticity, but their possible contribution to the protein synthesis-dependent processes underlying long-term synaptic plasticity and memory have not been examined. In the present application, conditional expression of a dominant-negative form of MEK1 in the post-natal murine forebrain is shown to inhibit ERK activation and cause selective deficits in hippocampal memory consolidation and the translation dependent, transcription independent phase of hippocampal LLTP. Translational studies in hippocampal neurons demonstrate that ERK inhibition blocks neuronal activity induced protein synthesis in a manner independent of cis-acting mRNA sequences. These results suggest a crucial role for translational control by ERK signaling in long-lasting forms of synaptic plasticity and memory. To extend these findings, the following hypotheses will be tested: 1) The ERK and mTOR pathways regulate protein synthesis in response to neuronal activity through phosphorylation of key components of the translational machinery; 2) ERK-dependent translational induction is required for the establishment of protein synthesis-dependent bidirectional synaptic plasticity, i.e. L-LTP and L LTD; 3) ERK dependent translational control plays an important role in the structural plasticity of dendritic spines. The career development program will be enhanced by collaborations with two senior investigators with expertise in the proposed investigations, Mark Bear and Morgan Sheng at MIT, and by attendance and presentation of results at local seminars and international conferences. Clinical work on memory disorders will complement the proposed research. The Neurology Department at MGH provides a rich and diverse scientific environment for the proposed career development plan, which will facilitate the establishment of a research program devoted to understanding the mechanisms of human cognition and cognitive disorders.