CONTROL OF PROTEIN SYNTHESIS-DEPENDENT SYNAPTIC PLASTIC

该计划的总体目标是了解学习和记忆基础上依赖于蛋白质合成的突触修饰。已经确定活性会刺激蛋白质合成，并且其中一些蛋白质是由位于突触或突触附近的 mRNA 合成的。研究人员最近描述了这种经验驱动的局部翻译的新机制，其中翻译休眠的突触 mRNA 通过 CPEB（细胞质多腺苷酸化元件结合蛋白）的作用进行多腺苷酸化。这一发现为研究局部 mRNA 翻译在突触可塑性中的作用提供了前所未有的机会，并为对蛋白质合成依赖性突触可塑性的调节进行连贯、综合和广泛的研究奠定了基础。项目 1 (Richter) 包括新 CPEB 亚型的表征以及使用 Cre-loxP 技术的新型靶向 CPEB 敲除小鼠；以及其他 CPEB 调节 mRNA 的鉴定。项目 2（Fallon）包括在光和电磁水平上定位 CPEB 在发育成人大脑和培养的海马神经元中的作用；从突触激活到细胞质聚腺苷酸化的细胞内信号传导途径的表征；以及含有 CPE 的 mRNA 和 CPEB 靶向树突的调节。项目 3（Bear）将表征蛋白质合成依赖性突触可塑性的诺埃尔形式（DHPG-LTD）；使用缺乏 CPEB 的小鼠进行巩固；并描述了局部翻译和 CPEB 在 NMDA 受体亚基表达的经验依赖性调节中的作用。将有两个核心，一个是行政核心，第二个用于生产和维护 CPEB 敲除小鼠，供所有研究人员使用。这些应该有助于更好地理解长期记忆形成的机制。研究结果可以提供了解影响学习和记忆的疾病所需的见解，并可能有助于设计对抗这些疾病的治疗策略。

The overall goal of this Program is to understand the protein synthesis- dependent synaptic modifications that underlie learning and memory. It has been established that activity stimulates protein synthesis, and that some of these proteins are synthesized from mRNA localized at or near the synapse. The investigators recently described a novel mechanism for such experience-driven local translation wherein translationally dormant synaptic mRNA is polyadenylated through the action of the CPEB (cytoplasmic polyadenylation element binding protein). This discovery provides an unprecedented opportunity to study the role of local mRNA translation in synaptic plasticity, and forms the basis for a coherent, integrated, and broadly-based investigation into the regulation of protein synthesis-dependent synaptic plasticity. Project 1 (Richter) includes the characterization of new CPEB isoforms and a novel targeted CPEB knock-out mouse using Cre-loxP technology; and the identification of additional CPEB-regulated mRNAs. Project 2 (Fallon) includes the localization, at the light and EM level, of CPEB in developing an adult brain, and in cultured hippocampal neurons; the characterization of the intracellular signaling pathways leading from synaptic activation to cytoplasmic polyadenylation; and the regulation of the targeting of CPE- containing mRNAs and of CPEB to dendrites. Project 3 (Bear) will characterize a noel form of protein synthesis-dependent synaptic plasticity (DHPG-LTD); use mice lacking CPEB in the consolidation; and characterize the role of local translation and CPEB in experience- dependent regulation of NMDA receptor subunit expression. There will be two cores, one administrative and the second for the production and maintenance of CPEB knock-out mice, which will be used by all the investigators. These should lead to better understanding of the mechanisms of long-term memory formation. The results could provide insights needed to understand diseases that affect learning and memory, and may be useful in designing therapeutic strategies to combat them.