Regulation of dopamine quantal size in midbrain and hippocampal neurons
Regulation of dopamine quantal size in midbrain and hippocampal neurons
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DOI：
10.1016/s0166-4328(01)00419-3
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发表时间：
2002-03-10
影响因子：
2.7
通讯作者：
Pothos, EN
中科院分区：
文献类型：
--
作者：
Pothos, EN
自从几十年前Bernard Katz和他的同事们的开创性工作以来，神经递质量子大小(定义为单个突触小泡在胞吐过程中释放的神经递质分子的数量)经常被建模为不变。这一假设对突触可塑性的基础研究具有重要意义。例如，在学习和记忆的研究中，它将注意力集中在突触后而不是突触前部分(脑海中的长时程增强领域就是最好的例子)。此外，这一假设以某种方式“溢出”到了对单胺类神经递质的研究中，与Katz研究的快速作用神经递质相比，单胺类神经递质显然使用扩散和慢速作用来发挥其调节作用。因此，对多巴胺相关疾病(如精神病和运动障碍)的研究没有对调节多巴胺释放的突触前机制给予那么多的关注，而对突触后受体的作用给予了那么多的关注。当然，部分问题是缺乏直接从突触前部位测量量子的技术，以及必须依赖微型突触后电位(MINI)的测量来得出关于突触前量子事件的结论。由于最初由波尔多大学的Francois Gonon和北卡罗来纳大学的Mark Wightman在组织电生理学中引入了碳纤维安培微电极，我们能够通过安培直接测量培养的中脑多巴胺神经元突起中的多巴胺量子。这是第一个提供直接测量中枢神经系统神经元终末突触前量子释放分子数量和动力学的方法。到目前为止，改变多巴胺量子大小的干预措施如下。(1)神经递质合成的改变-胞质多巴胺可获得性增加(例如，暴露于L-多巴)增加量子大小，而胞质多巴胺因D2自身受体激活而减少(通过喹比罗)减小量子大小。(2)囊泡递质转运体活性的调节-神经元囊泡单胺转运体VMAT2的过表达增加了多巴胺的量子大小。小鼠体内VMAT2蛋白的减少或消除显著阻碍或消除了单胺的释放。(3)再摄取阻滞剂--可卡因和氨基甲酸是多巴胺再摄取阻滞剂，它们能独立于D2相关效应减小量子大小。(4)跨泡pH梯度-神经元刺激的改变明显通过激活囊泡膜上的氯通道和增大量子大小而导致囊泡酸化。(5)融合毛孔动力学--在回收之前，经历胞吐作用的囊泡可能只排出部分神经递质。因此，融合孔形状的可塑性可能是量子大小的关键决定因素，量子大小变化的其他可能来源是递质脱颗粒和突触小泡体积的变化。我们认为多巴胺量子的可塑性似乎可能与正常的突触改变和疾病状态有关，(C)2002 Elsevier Science B.V.保留所有权利。
Since the pioneering work of Bernard Katz and his colleagues decades ago, neurotransmitter quantal size (defined as the number of neurotransmitter molecules released by a single synaptic vesicle during exocytosis) is often modeled as invariant. This assumption had tremendous implications for basic research on synaptic plasticity. For instance, it focused attention on the postsynaptic rather than the presynaptic component in studies of learning and memory (the field of long-term potentiation comes to mind as the best example). Furthermore, this assumption somehow 'spilled over' onto studies of monoamine neurotransmitters, which apparently use diffusion and slow action to exert their modulatory effects, in contrast to the fast acting neurotransmitters studied by Katz. Consequently, research on dopamine-related diseases (e.g. psychotic and movement disorders) did not pay as much attention to presynaptic mechanisms that regulate dopamine release, as to postsynaptic receptor action. Part of the problem, of course, has been the lack of technology to directly measure quanta from presynaptic sites and the obligatory reliance on measurements of miniature postsynaptic potentials (minis) for reaching conclusions about presynaptic quantal events. Due to the introduction of the carbon fiber amperometric microelectrode in tissue electrophysiology, initially by Francois Gonon (University of Bordeaux) and then by Mark Wightman (University of North Carolina), we were able to directly measure dopamine quanta from neurites of cultured midbrain dopamine neurons by amperometry. This was the first approach to provide direct measurement of the number of molecules and kinetics of presynaptic quantal release from CNS neuronal terminals. The interventions altering dopamine quantal size are so far the following. (1) Alteration of neurotransmitter synthesis-an increase of cytosolic dopamine availability (e.g. by exposure to L-DOPA) increases quantal size and a decrease of cytosolic dopamine by D2 autoreceptor activation (by quinpirole) decreases quantal size. (2) Modulation of vesicle transmitter transporter activity - overexpression of the neuronal vesicular monoamine transporter VMAT2 increases dopamine quantal size. The reduction or elimination of VMAT2 protein in mice significantly hampers or eliminates monoamine release. (3) Reuptake blockade-cocaine and amfonelic acid are dopamine reuptake blockers which reduce quantal size independently of D2-related effects. (4) Changes in transvesicular pH gradient-neuronal stimulation apparently leads to vesicular acidification via the activation of chloride channels on the vesicular membrane and increased quantal size. (5) Fusion pore kinetics-a vesicle undergoing exocytosis may discharge only part of its neurotransmitter content before recycling. Plasticity of the fusion pore shape may, therefore, be a crucial determinant of quantal size, Other possible sources of variability in quantal size are altered transmitter degranulation and changes in synaptic vesicle volume. We suggest that plasticity in dopamine quantal seems likely to be involved in both normal synaptic modification and disease states, (C) 2002 Elsevier Science B.V. All rights reserved.