Study of the Vesicular Monoamine Transporter: Role and Function

囊泡单胺转运蛋白的研究：作用和功能

• 批准号: 385732-2012
• 负责人: Giros, Bruno
• 金额: $ 1.89万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=572898
• 关键词: Study; Vesicular; Monoamine; Transporter; Role

Synthesized in only a few restricted nuclei in the brain, the three monoamines (MA) neurotransmitters, dopamine, serotonin and noradrenalin, are altogether the major regulators of almost all superior brain functions. The importance of MA neurotransmission is highlighted by their direct implication in functions as diversed as sleep processes, executive functions, learning and memory, pain, anxiety, arousal, motivation, locomotor control, reward, etc etc.... At the present time, more than 80% of psychotropic or recreative drugs that are used, are directly targeting receptors or transporters specific for these three monoamines. Only one vesicular transporter, the vesicular monoamine transporter (VMAT2) is accumulating MA in their specific vesicles, that will be further released from the nerve terminals, to activates the various receptors. Therefore, the VMAT2 controls MA concentration in the terminals, and the intensity of the monoamine release at the synapse. However, because the same VMAT2 is present in all MA terminals, dopamine, serotonin or noradrenalin, it is not possible to study each system separately, and therefore to be able to understand how the control of transmitter fluxes, and the balance between these three MA systems, is possibly involved to regulates brain functions. We have now produced a genetic mouse model allowing, for the first time, the conditional suppression of VMAT2 in specific neuronal subsets, or at specific times during development and adulthood. This model will now allow us, within the next years, to unravel these very important questions, and to have eventually a better understanding of the respective role and circuits of these three intermingled and essential neurotranmitter systems.

三种单胺（MA）神经递质，多巴胺、5-羟色胺和去甲肾上腺素，仅在大脑中少数几个有限的核团中合成，是几乎所有上级大脑功能的主要调节剂。MA神经传递的重要性突出表现在它们对睡眠过程、执行功能、学习和记忆、疼痛、焦虑、唤醒、动机、运动控制、奖励等多种功能的直接影响。目前，超过80%的精神药物或娱乐药物直接靶向这三种单胺的受体或转运蛋白。 只有一种囊泡转运蛋白，囊泡单胺转运蛋白（VMAT 2）在其特定的囊泡中积累MA，这些囊泡将进一步从神经末梢释放，以激活各种受体。因此，VMAT 2控制着末梢中的MA浓度和突触处单胺释放的强度。然而，由于相同的VMAT 2存在于所有MA终端，多巴胺，5-羟色胺或去甲肾上腺素中，因此不可能单独研究每个系统，因此能够理解如何控制递质通量，以及这三个MA系统之间的平衡，可能涉及调节大脑功能。 我们现在已经产生了一种遗传小鼠模型，首次允许在特定的神经元亚群中或在发育和成年期间的特定时间有条件地抑制VMAT 2。在未来几年内，这个模型将使我们能够解开这些非常重要的问题，并最终更好地理解这三个相互混合的基本神经传导系统各自的作用和回路。