Mechanisms and Functions of Presynaptic Plasticity

突触前可塑性的机制和功能

• 批准号: 7283686
• 负责人: Craig C Garner
• 金额: $ 130.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-05 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7283686
• 关键词: Mechanisms; Functions; Presynaptic; Plasticity

DESCRIPTION (provided by applicant): Long-lasting neural circuit modifications are thought to underlie all forms of adaptive and pathological experience-dependent plasticity. Thus there has been great interest in elucidating the mechanisms and functions of various forms of synaptic plasticity. While historically NMDA receptor-dependent long-term potentiation (LTP) has been the prototypic and most extensively studied form of long-lasting synaptic plasticity, it is clear that several key circuits in the mammalian brain express an NMDA receptor-independent form of LTP that is triggered by increases in cAMP and mediated by a long-lasting enhancement of neurotransmitter release. The central goal of this program project is to elucidate the molecular mechanisms and functions of this presynaptic form of LTP. This will be accomplished by analyzing the functional properties of the presynaptic active zone protein RIM to both presynaptic forms of plasticity as well as its contribution to learning and memory in the cerebellum. We have assembled four projects to accomplish these goals. In project #1, we propose a biochemical and genetic analysis of RIM to elucidate the contributions that individual RIM isoforms and domains make to RIM function. In project #2, we will utilize electrophysiological approaches to assess the physiological functions of RIM isoforms and discrete RIM domains to different forms of presynaptic plasticity. In project #3, we propose a set of cellular and dynamic imaging studies to examine how RIM proteins regulate the dynamics of key active zone proteins in response to synaptic activity. Finally, in project #4, we proposed to integrate these RIM structure function studies to assess the role that presynaptic forms of plasticity contribute to VOR plasticity in the mouse cerebellum. These studies will advance our understanding of not only how RIM proteins regulate neurotransmitter release, but also how presynaptic forms of long-lasting plasticity contribute to both neural circuit behavior and experience dependent plasticity.

描述（由申请人提供）：持久的神经回路修饰被认为是各种形式的适应性和病理经验依赖性可塑性的基础。 因此，人们对阐明各种突触可塑性的机制和功能引起了极大的兴趣。 虽然历史上NMDA受体依赖性长期增强（LTP）一直是长期持久突触可塑性的原型，最广泛研究的形式，但很明显，哺乳动物大脑中的几个关键电路表达了NMDA受体受体与LTP的LTP形式，这是由LTP的LTP形式通过camps seled septers septers nepriment sehlist and plastiment sehlist sehlist neprants neprants neprants neprants neprants neprants sehland asterments neprants s的增强而造成的。 该计划项目的核心目标是阐明这种突触前LTP的分子机制和功能。 这将通过分析突触前活性区蛋白边缘的功能特性来实现，这两种形式的可塑性及其对小脑学习和记忆的贡献。 我们组装了四个项目来实现这些目标。 在项目＃1中，我们提出了RIM的生化和遗传分析，以阐明单个边缘同工型和域对RIM功能的贡献。 在项目＃2中，我们将利用电生理方法评估不同形式的突触前可塑性的边缘同工型和离散边缘域的生理功能。 在项目＃3中，我们提出了一组细胞和动态成像研究，以检查RIM蛋白如何调节关键活性区蛋白的动力学对突触活性的响应。 最后，在项目＃4中，我们提议将这些边缘结构函数研究整合在一起，以评估突触前可塑性的作用，从而有助于小脑小脑的可塑性。 这些研究不仅会提高我们对RIM蛋白如何调节神经递质释放的理解，而且还会提高我们对持久可塑性的突触前形式如何有助于神经回路行为和依赖经验的可塑性。