Study of the Vesicular Monoamine Transporter: Role and Function

三种单胺类神经递质--多巴胺、5-羟色胺和去甲肾上腺素--在大脑中仅有少数几个限制性核团合成，是几乎所有高级大脑功能的主要调节物质。MA神经传递的重要性被它们在睡眠过程、执行功能、学习和记忆、疼痛、焦虑、觉醒、动机、运动控制、奖励等不同功能中的直接含义所突显。目前，80%以上的精神药物或娱乐药物直接针对这三种单胺的受体或转运体。 只有一种囊泡转运体，即囊泡单胺转运体(VMAT2)，在其特定的囊泡中积累MA，并从神经末梢进一步释放，以激活各种受体。因此，VMAT2控制着终末的MA浓度和突触上单胺的释放强度。然而，由于相同的VMAT2存在于所有MA终末、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，从而能够理解这三个MA系统之间的平衡是如何参与调节大脑功能的。 我们现在已经创造了一个遗传的小鼠模型，首次允许在特定的神经元亚群中或在发育和成年期的特定时间有条件地抑制VMAT2。这个模型现在将允许我们在未来几年内解开这些非常重要的问题，并最终更好地理解这三个相互交织的基本神经传递系统的各自作用和回路。

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.