Ultrafast membrane trafficking at synapses

项目摘要 突触处的神经元信号事件决定电路反应，并导致特定的行为输出。 这种信号是由突触活动史和感知刺激动态调节的。中的缺陷 神经传递在神经性疾病中也起着致病作用。然而，我们对此的理解 流程受到两个因素的限制：大小和速度。多年来，我们在以下方面开发了几种技术 电子显微镜观察与脑缺血相关的蛋白质定位和突触超微结构的变化 具有毫秒时间精度的神经元活动。我们的实验揭示了对 突触小泡周期的机制以及控制突触可塑性的新参数。然而， 许多谜团依然存在。胞外和胞内蛋白如何协同介导膜重塑 在毫秒时间尺度上的突触？这些蛋白质是如何相互作用和膜脂的？ 来履行他们的职能？这些过程的异质性有多大？为了解决这些问题，我们将 开发电子显微镜的新方法，并利用这些工具来剖析分子 突触小泡胞吐和胞吞的机制。

Project Summary Neuronal signaling events at synapses determine circuit responses and result in specific behavioral outputs. This signaling is dynamic - modulated by the history of synaptic activity and perceived stimuli. Defects in neurotransmission also play a causative role in neurological disorders. However, our understanding of this process is limited by two factors: size and speed. Over the years, we have developed several techniques in electron microscopy to visualize changes in protein localization and synaptic ultrastructure associated with neuronal activity with millisecond temporal precision. Our experiments have revealed key insights into mechanisms of the synaptic vesicle cycle as well as new parameters controlling synaptic plasticity. However, many mysteries remain. How do exocytic and endocytic proteins coordinate to mediate membrane remodeling at synapses on a millisecond time scale? How do these proteins interact with each other and membrane lipids to perform their functions? How heterogenous are these processes? To address these questions, we will develop novel approaches in electron microscopy and leverage these tools to dissect the molecular mechanisms underlying synaptic vesicle exocytosis and endocytosis.