CONTROL OF PROTEIN SYNTHESIS-DEPENDENT SYNAPTIC PLASTIC

该计划的总体目标是了解蛋白质合成依赖的突触修饰，这是学习和记忆的基础。已经确定，活动刺激蛋白质合成，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（细胞质聚腺苷化元件结合蛋白）的作用被聚腺苷化。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，并为连贯、综合、广泛地研究蛋白质合成依赖性突触可塑性的调节奠定了基础。项目1 （Richter）包括新的CPEB亚型的表征和使用Cre-loxP技术的新型靶向CPEB敲除小鼠；以及其他cpeb调控mrna的鉴定。项目2 （Fallon）包括在光和EM水平上定位CPEB在发育中的成人大脑和培养的海马神经元；从突触激活到胞质聚腺苷酸化的胞内信号通路的表征以及含CPE的mrna和CPEB对树突的靶向调控。项目3 （Bear）将描述一种新形式的蛋白质合成依赖性突触可塑性（DHPG-LTD）；使用CPEB缺失小鼠进行巩固；并描述局部翻译和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，一个是行政中心，另一个是CPEB基因敲除小鼠的生产和维护中心，供所有研究人员使用。这将有助于我们更好地理解长期记忆形成的机制。研究结果可以为理解影响学习和记忆的疾病提供必要的见解，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.