Mechanisms of Synaptic Transmission in Healthy and Disease States

健康和疾病状态下突触传递的机制

• 批准号: 9924659
• 负责人: Vitaly A Klyachko
• 金额: $ 73.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9924659
• 关键词: Actins; Active Sites; Address; Area; Behavior; Biochemical; Biological Assay; Cognition; Complex; Cytoskeleton; Defect; Diagnostic; Disease; Electrons; Electrophysiology (science); Fragile X Syndrome; Functional disorder; Funding; Goals; Heritability; Imaging technology; Intellectual functioning disability; Knowledge; Lead; Link; Motor; Movement; Myosin ATPase; Neurobiology; Play; Process; Recycling; Research; Resolution; Role; Synapses; Synaptic Transmission; Synaptic Vesicles; Technology; Therapeutic; Time; Tissues; Vesicle; Work; autism spectrum disorder; base; dynamic system; innovation; light microscopy; nanoscale; novel; postsynaptic; presynaptic; programs; spatiotemporal; synergism; translational impact

Direct examination of presynaptic processes has historically been limited by the resolution constraints of conventional light microscopy. As a result, much of what we know about vesicle movement, fusion, and recycling relies on inferences from indirect electrophysiological and/or biochemical assays, or from electron micrographs that reflect a single instant of a dynamic system. The long-term goal of my research program is to understand the fundamental mechanisms of synaptic transmission at central synapses, including details of spatiotemporal dynamics under normal conditions, and what disruptions lead to disease states. Current projects in the lab address two central knowledge gaps. First, we directly probe and track dynamic presynaptic processes in living tissue by applying our own novel, nanoscale resolution imaging technology. Using this approach, we will, for the first time, visualize these processes at the level of single synaptic vesicles within identified synapses. We have already made significant contributions using this approach, including the discovery that synaptic vesicle dynamics are active, not passive, and are controlled by actin cytoskeleton and myosin motors. The second major knowledge gap we address is the contribution of presynaptic deficits to pathophysiology of Fragile X syndrome (FXS). FXS is the most common known cause of heritable intellectual disability and autism. Our recent findings have triggered a necessary shift in the field towards considering the contributions of presynaptic mechanisms in addition to postsynaptic mechanisms, thus creating an entirely new array of diagnostic and therapeutic possibilities. Continuing work in this area will focus on linking presynaptic defects with abnormalities at the circuit level and the implications of these abnormalities for behavior and cognition. Sustained funding through this R35 mechanism will support a multipronged approach to these important neurobiological questions that will maximize the potential for synergy and translational impact.

对突触前过程的直接检查历来受到以下分辨率限制： 常规光学显微镜。因此，我们所知道的关于囊泡运动、融合和 再循环依赖于来自间接电生理学和/或生物化学测定的推断，或来自电子 反映动态系统的一个瞬间的显微照片。我的研究计划的长期目标是 了解在中央突触突触传递的基本机制，包括细节， 正常情况下的时空动态，以及什么样的破坏导致疾病状态。电流 实验室中的项目解决了两个核心知识差距。首先，我们直接探测和跟踪动态突触前 通过应用我们自己的新颖的纳米级分辨率成像技术，使用此 方法，我们将首次在单个突触囊泡的水平上可视化这些过程， 识别突触。我们已经使用这种方法做出了重大贡献，包括 发现突触囊泡动力学是主动的，而不是被动的，并由肌动蛋白细胞骨架控制， 肌球蛋白马达。我们要解决的第二个主要知识缺口是突触前缺陷对 脆性X综合征（FXS）的病理生理学。FXS是最常见的已知原因遗传性智力障碍 残疾和自闭症。我们最近的发现引发了该领域的必要转变， 除了突触后机制外，突触前机制的贡献，从而创造了一个全新的 诊断和治疗的可能性。在这一领域的持续工作将集中在连接突触前 电路水平异常的缺陷以及这些异常对行为的影响， 认知.通过这一R35机制持续供资将支持采取多管齐下的办法， 重要的神经生物学问题，将最大限度地发挥潜力的协同作用和翻译的影响。