Molecular Organization of CNS Synapses

中枢神经系统突触的分子组织

• 批准号: 6639494
• 负责人: MORGAN H. SHENG
• 金额: $ 24.83万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639494
• 关键词: AMPA receptors; endocytosis; excitatory aminoacid; hippocampus; immunocytochemistry; intracellular transport; matrix assisted laser desorption ionization; neural transmission; protein protein interaction; protein transport; receptor binding; receptor expression; synapses; thrombin

DESCRIPTION (provided by applicant): Excitatory synaptic transmission in the mammalian brain is primarily mediated by the neurotransmitter glutamate acting on two classes of postsynaptic glutamate receptors: NMDA receptors and AMPA receptors (NMDARs and AMPARs). Our long-term objective is to understand the molecular mechanisms by which glutamate receptors are targeted to the postsynaptic membrane and how these mechanisms can be regulated to control the strength of synaptic transmission. This proposal therefore addresses a fundamental issue in synaptic plasticity, which is of relevance to brain development and to learning and memory. Recent studies suggest that regulated trafficking of postsynaptic AMPARs is a major mechanism underlying the long-lasting potentiation and depression of synaptic transmission. However, the cell biological events have only been superficially (and largely qualitatively) described, and the underlying molecular mechanisms remain poorly understood. To address these important questions, we will use quantitative immunocytochemical and biochemical techniques to comprehensively investigate AMPAR internalization (endocytosis) and insertion (exocytosis) in cultured hippocampal neurons. The molecular mechanisms by which AMPAR internalization/insertion is regulated by synaptic activity and growth factors will be studied with subunits GluR1 and GluR2. The site of new AMPAR insertion in the neuronal surface will be visualized at high resolution. In addition, we will search for and functionally characterize novel AMPAR-binding proteins that may play a role in AMPAR trafficking, and hence synaptic plasticity. Finally, the functional significance of the molecular findings will be tested by electrophysiological experiments in hippocampal slices. In each of these aims, we have strong Preliminary Data that substantiate the significance and that demonstrate the feasibility of the proposed experiments. Because glutamate receptor function is intimately involved in brain synaptic function and excitotoxicity, this research may be relevant to human acute and chronic neurodegenerative disease and to psychiatric disorders.

描述（申请人提供）：兴奋性突触传播 哺乳动物大脑主要由神经递质谷氨酸作用介导 在两类突触后谷氨酸受体上：NMDA受体和AMPA 受体（NMDAR和AMPAR）。我们的长期目标是了解 谷氨酸受体针对的分子机制 突触后膜以及如何调节这些机制以控制 突触传播的强度。因此，该提议解决了 突触可塑性的基本问题，这与大脑有关 发展，学习和记忆。 最近的研究表明，调节突触后AMPAR的贩运是一种 持久的增强和抑郁的主要机制 突触传输。但是，细胞生物事件仅是 从表面上（质量上的）描述了基础 分子机制仍然很少理解。解决这些重要的 问题，我们将使用定量免疫细胞化学和生化 全面研究AMPAR内在化的技术（内吞） 和培养的海马神经元中的插入（胞吐作用）。分子 AMPAR内在化/插入受到突触调节的机制 活性和生长因子将使用Glur1和Glur2的亚基研究。这 新的AMPAR插入位点在神经元表面的位置将在高处可视化 解决。此外，我们将搜索并在功能上表征新颖 可能在AMPAR贩运中发挥作用的AMPAR结合蛋白，因此 突触可塑性。最后，分子的功能意义 发现将通过海马的电生理实验测试 切片。在每个目标中，我们都有强大的初步数据 证实了意义，并证明了 提出的实验。 因为谷氨酸受体功能与大脑突触密切相关 功能和兴奋性，这项研究可能与人类的急性有关 慢性神经退行性疾病和精神疾病。