Translational Control in Long-Term Synaptic Plasticity

描述(由申请人提供)：神经生物学中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。对这些机制的洞察将对人类认知和神经精神疾病具有广泛的相关性。持久的突触可塑性和记忆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，但它们在长期突触可塑性和记忆所依赖的蛋白质合成过程中的可能作用尚未被研究。在目前的应用中，在出生后的小鼠前脑中有条件地表达显性-负性形式的MEK1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、转录非依赖阶段的选择性缺陷。海马神经元的翻译研究表明，ERK抑制以一种独立于顺式作用的mRNA序列的方式阻断神经元活动诱导的蛋白质合成。这些结果表明，ERK信号在突触的长期可塑性和记忆中的翻译控制中起着至关重要的作用。为了推广这些发现，我们将检验以下假设：1)ERK和mTOR通路通过磷酸化翻译机制的关键组件来调节蛋白质的合成，以响应神经元的活动；2)ERK依赖的翻译诱导是建立蛋白质合成依赖的双向突触可塑性所必需的，即L-LTP和L有限公司；3)ERK依赖的翻译控制在树突棘的结构可塑性中发挥重要作用。职业发展计划将通过与两名在拟议调查方面具有专业知识的高级调查人员--麻省理工学院的马克·贝尔和摩根·盛--合作，以及通过出席当地研讨会和国际会议并展示结果来加强。有关记忆障碍的临床工作将补充这项拟议的研究。麻省理工学院神经病学系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.