Mechanisms and Functions of Presynaptic Plasticity

描述(申请人提供)：持久的神经回路改变被认为是所有形式的适应性和病理性经验依赖性可塑性的基础。因此，人们对阐明各种形式突触可塑性的机制和功能产生了极大的兴趣。虽然历史上NMDA受体依赖的长时程增强(LTP)一直是长时间突触可塑性的原型和最广泛研究的形式，但很明显，哺乳动物大脑中的几个关键回路表达一种NMDA受体非依赖形式的LTP，该形式由cAMP增加触发，并由神经递质释放的长期增强介导。这个项目的中心目标是阐明这种突触前形式LTP的分子机制和功能。这将通过分析突触前活动区蛋白RIM对突触前可塑性的功能特性以及它对小脑学习和记忆的贡献来实现。我们已经组织了四个项目来实现这些目标。在项目1中，我们建议对RIM进行生化和遗传分析，以阐明单个RIM异构体和结构域对RIM功能的贡献。在项目2中，我们将利用电生理学方法来评估RIM异构体和离散的RIM结构域对不同形式的突触前可塑性的生理功能。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动区蛋白的动力学以响应突触活动。最后，在项目#4中，我们建议整合这些RIM结构功能研究，以评估突触前可塑性形式对小鼠小脑VOR可塑性的作用。这些研究不仅将促进我们对RIM蛋白如何调节神经递质释放的理解，还将促进我们对突触前形式的长期可塑性如何促进神经回路行为和经验依赖性可塑性的理解。

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.