Modulation of Synaptic Vesicles in Neurotransmission, Plasticity and Addiction

描述（由申请人提供）：临床和实验室数据一致认为，药物成瘾是对突触可塑性的篡夺，突触可塑性通常支持奖励相关的学习和记忆。例如，反复接触可卡因会导致奖赏学习的神经回路产生多种形式的突触可塑性。突触可塑性是指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反应的有效程度的变化。由于药理学和电生理工具具有高选择性和敏感性，我们对突触后可塑性的看法得到了很大的发展。然而，与成瘾密切相关的突触前可塑性却很少得到重视，部分原因是缺乏直接监测突触囊泡释放神经递质的方法。利用其纳米级尺寸和优越的光特性，我开发了一种基于量子点的方法，可以直接报告培养海马神经元中单个突触前囊泡的行为，时间长达几分钟甚至几小时。我发现高释放概率的囊泡更倾向于快速和可逆的重复使用模式（kiss-and-run, K&R），并且通过K&R的增加来增强神经传递。为了解药物成瘾如何改变突触囊泡的融合和恢复以及突触前神经递质释放，我建议：(1)研究与突触前可塑性相关的囊泡释放修饰，(2)确定介导突触前可塑性的囊泡释放蛋白调节因子，(3)阐明多巴胺的囊泡释放是如何调节的以及成瘾药物如何影响多巴胺的囊泡释放。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重要性，了解突触囊泡在药物成瘾中的功能失调可能有助于治疗社会上最棘手的健康问题之一。

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.