CONTROL OF PROTEIN SYNTHESIS-DEPENDENT SYNAPTIC PLASTIC

蛋白质合成依赖的突触塑料的控制

• 批准号: 6027316
• 负责人: JUSTIN R. FALLON
• 金额: $ 83.95万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-10 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6027316
• 关键词: RNA binding protein; neural plasticity; polyadenylate; protein biosynthesis

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.

这个项目的总体目标是了解蛋白质合成依赖的突触修饰，它是学习和记忆的基础。已经确定，活动刺激蛋白质合成，并且这些蛋白质中的一些是从位于突触处或附近的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，其中通过CPEB（细胞质聚腺苷酸化元件结合蛋白）的作用，突触休眠mRNA被聚腺苷酸化。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，并形成了对蛋白质合成依赖性突触可塑性调节进行连贯、综合和广泛研究的基础。项目1（Richter）包括使用Cre-loxP技术表征新的CPEB亚型和新的靶向CPEB敲除小鼠;以及鉴定其他CPEB调节的mRNA。项目2（Fallon）包括在光和EM水平下，CPEB在发育成脑中和在培养的海马神经元中的定位;从突触活化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到树突的靶向的调节。项目3（Bear）将表征蛋白质合成依赖性突触可塑性（DHPG-LTD）的诺埃尔形式;在巩固中使用缺乏CPEB的小鼠;并表征局部翻译和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，另一个是用于生产和维持CPEB敲除小鼠的核心，所有研究者都将使用。这将有助于更好地理解长期记忆形成的机制。这些结果可以为理解影响学习和记忆的疾病提供所需的见解，并可能有助于设计治疗策略来对抗它们。