Modulation of Synaptic Vesicles in Neurotransmission, Plasticity and Addiction

描述（由申请人提供）：临床和实验室数据已经集中在这样一个观点上，即药物成瘾是对通常支持奖励相关学习和记忆的突触可塑性的篡夺。例如，重复的可卡因暴露在奖励学习的神经元回路中诱导多种形式的突触可塑性。突触可塑性是两个神经元之间的连接或突触强度变化的能力。它包括突触前神经递质释放量的变化和突触后细胞对这些神经递质的有效反应的变化。高选择性和高灵敏度的药理学和电生理学工具的出现，使我们对突触后可塑性的认识有了很大的进展。然而，突触前可塑性，也密切参与成瘾，是不太赞赏，部分原因是缺乏直接监测突触囊泡释放神经递质的方法。利用其纳米尺寸和上级光特性，我开发了一种基于量子点的方法，可以直接报告培养的海马神经元中单个突触前囊泡的行为，持续数分钟甚至数小时。我发现具有高释放概率的囊泡更喜欢快速和可逆的再利用模式（吻和跑，K&R），并且通过增加K&R来实现神经传递的增强。为了了解突触囊泡的融合和恢复以及神经递质的突触前释放在药物成瘾中是如何改变的，我建议：（1）研究与突触前可塑性相关的囊泡释放的修饰，（2）鉴定介导突触前可塑性的囊泡释放的蛋白质调节剂，以及（3）说明了多巴胺的囊泡释放是如何被调节的以及成瘾药物是如何影响它的。鉴于突触囊泡在突触前可塑性中的重要性以及突触前可塑性在药物成瘾中的意义，了解突触囊泡如何在药物成瘾中发生故障，可能有助于治疗社会上最棘手的健康问题之一。 公共卫生部门：本项目旨在探索调节突触前末梢神经传递的分子和细胞机制，并了解它们如何被成瘾物质干扰。它将促进我们对药物成瘾的神经学基础的了解，这与国家药物滥用研究所的使命是一致的。

DESCRIPTION (provided by applicant): Clinical and laboratory data have converged on the idea that drug addiction is the usurpation of synaptic plasticity that normally supports reward-related learning and memory. For example, repeated cocaine exposure induces multiple forms of synaptic plasticity in the neuronal circuitry for reward learning. Synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength. It includes presynaptic change on the quantity of neurotransmitter released and postsynaptic change on how effectively cells respond to those neurbtransmitters. Our view of post -synaptic plasticity is greatly advanced owing to pharmacological and electrophysiological tools with high selectivity and sensitivity. However, presynaptic plasticity, also closely involved in addiction, is less appreciated, in part due to the lack of ways to directly monitor synaptic vesicles releasing neurotransmitter. Taking advantage of its nanoscale size and superior photoproperties, I developed a quantum -dot-based approach that can directly report the behavior of single presynaptic vesicles in cultured hippocampal neurons for minutes or even hours. I discovered that vesicles with high release probability prefer a mode of fast and reversible reuse (kiss-and-run, K&R) and the potentiation of neurotransmission was achieved by the increase of K&R. To understand how the fusion and retrieval of synaptic vesicles and the presynaptic release of neurotransmitter are altered in drug addiction, I propose to: (1) investigate the modification of vesicle release associated with presynaptic plasticity, (2) identify the protein regulators of vesicle release that mediate presynaptic plasticity, and (3) illustrate how vesicular release of dopamine is regulated and how addictive drugs affect it. Given the importance of synaptic vesicles in presynaptic plasticity and the significance of presynaptic plasticity in drug addiction, understanding how synaptic vesicles are malfunctioned in drug addiction may prove beneficial in the treatment of one of society's most intractable health problems. PUBLIC HEALTH REVELANCE: This project aims to explore the molecular and cellular mechanisms that regulate neurotransmission in the presynaptic terminals and to understand how they are perturbed by addictive substances. It will advance our knowledge about the neurological foundation of drug addiction, which is well aligned with the mission of the National Institute of Drug Abuse.