Translational Control in Long-Term Synaptic Plasticity

描述（由申请人提供）：神经生物学中的一个核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，但对潜在的调节机制知之甚少。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背后的蛋白质合成依赖过程的可能贡献尚未得到研究。在目前的应用中，在出生后的小鼠前脑中，MEK1的显性阴性形式的条件表达被证明可以抑制ERK的激活，并导致海马记忆巩固和海马LLTP的翻译依赖、转录独立阶段的选择性缺陷。海马神经元的翻译研究表明，ERK抑制以独立于顺式作用mRNA序列的方式阻断神经元活性诱导的蛋白质合成。这些结果表明，ERK信号在突触可塑性和记忆的长期形式中的翻译控制起着至关重要的作用。为了扩展这些发现，我们将测试以下假设：1)ERK和mTOR通路通过磷酸化翻译机制的关键组分来调节蛋白质合成以响应神经元活动；2)蛋白质合成依赖的双向突触可塑性，即L- ltp和L LTD的建立需要erk依赖的翻译诱导；3) ERK依赖的平移控制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Mark Bear和Morgan Sheng两位在拟议调查方面具有专业知识的高级调查员的合作，以及参加当地研讨会和国际会议并展示结果来加强。关于记忆障碍的临床工作将补充拟议的研究。MGH神经内科为提出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理解人类认知和认知障碍机制的研究项目。

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.