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，毒瘾是对突触可塑性的篡夺，而突触可塑性通常支持与奖励相关的学习和记忆。例如，反复接触可卡因会在用于奖赏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。它包括突触前对神经递质释放数量的变化和突触后细胞对这些神经递质反应的有效性的变化。由于药物和电生理工具的高度选择性和敏感性，我们对突触后可塑性的看法有了很大的进步。然而，突触前的可塑性，也与成瘾密切相关，人们对此认识较少，部分原因是缺乏直接监测突触小泡释放神经递质的方法。利用它的纳米尺寸和优越的光特性，我开发了一种基于量子点的方法，可以直接报告培养的海马神经元中单个突触前小泡的行为，时间长达几分钟甚至几个小时。我发现高释放率的囊泡倾向于一种快速可逆的再利用模式(KISS-and-Run，K&R)，神经传递的增强是通过K&R的增加实现的。为了了解药物成瘾中突触小泡的融合和恢复以及突触前神经递质的释放是如何改变的，我建议：(1)研究与突触前可塑性相关的囊泡释放的改变，(2)确定介导突触前可塑性的囊泡释放的蛋白质调节器，以及(3)阐明囊泡释放多巴胺是如何受到调节的，以及成瘾药物是如何影响它的。鉴于突触小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，了解突触小泡在药物成瘾中是如何发生故障的可能被证明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.