Mechanisms of Synaptic Transmission in Healthy and Disease States

对突触前过程的直接检查历来受到以下分辨限制的限制 常规光学显微镜。因此，我们所知道的关于囊泡运动、融合和 回收依赖于间接电生理和/或生化分析的推论，或电子推论。 反映动态系统的单个瞬间的显微照片。我的研究计划的长期目标是 了解中枢突触的突触传递的基本机制，包括 正常情况下的时空动力学，以及什么干扰会导致疾病状态。当前 实验中的项目解决了两个主要的知识差距。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的纳米分辨率成像技术在活组织中进行处理。使用这个 方法，我们将第一次在单个突触小泡的水平上可视化这些过程 识别出突触。我们已经使用这种方法做出了重大贡献，包括 发现突触小泡的动力学是主动的，而不是被动的，并由肌动蛋白细胞骨架和 肌球蛋白马达。我们解决的第二个主要知识差距是突触前缺陷对 脆性X综合征的病理生理学研究FXS是可遗传知识分子最常见的已知原因 残疾和自闭症。我们最近的发现引发了该领域的必要转变，转向考虑 除了突触后机制之外，突触前机制的贡献，从而创造了一个全新的 一系列诊断和治疗的可能性。这一领域的持续工作将侧重于将突触前 具有电路水平异常的缺陷以及这些异常对行为和 认知力。通过R35机制提供的持续资金将支持多管齐下解决这些问题 重要的神经生物学问题，将最大限度地发挥协同作用和翻译影响的潜力。

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.