Philippart Fabian, Destreel Geoffrey, Merino-Sepúlveda Paulina, Henny Pablo, Engel Dominique, Seutin Vincent
Neurophysiology Unit, GIGA Neurosciences, University of Liège, B-4000 Liège, Belgium, and.
Departamento de Anatomía Normal, Escuela de Medicina, and Centro Interdisciplinario de Neurociencias, Pontificia Universidad Católica de Chile, Santiago, Chile.
J Neurosci. 2016 Jul 6;36(27):7234-45. doi: 10.1523/JNEUROSCI.0459-16.2016.
Dopaminergic (DA) neurons located in the ventral midbrain continuously generate a slow endogenous pacemaker activity, the mechanism of which is still debated. It has been suggested that, in the substantia nigra pars compacta (SNc), the pacemaking relies more on Ca(2+) channels and that the density of L-type Ca(2+) channels is higher in these DA neurons than in those located in the ventral tegmental area (VTA). This might lead to a higher Ca(2+) load in SNc DA neurons and explain their higher susceptibility to degeneration. However, direct evidence for this hypothesis is lacking. We found that the L-type current and channel density are indeed higher in the somata of rat SNc DA neurons and that this current undergoes less inactivation in this region. Nonstationary fluctuation analysis measurements showed a much higher number of L-type channels in the soma of SNc DA neurons, as well as a smaller single-channel conductance, pointing to a possible different molecular identity of L-type channels in DA neurons from the two areas. A major consequence of this is that pacemaking and, even more so, bursting are associated with a larger Ca(2+) entry through L-type channels in SNc DA neurons than in their VTA counterparts. Our results establish a molecular and functional difference between two populations of midbrain DA neurons that may contribute to their differential sensitivity to neurodegeneration.
Dopamine neurons from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are involved in various brain functions, such as movement initiation and goal directed behavior, respectively. This work shows that, although both neurons fire in a similar regular and slow pacemaker mode, this firing activity is supported by different calcium channel landscapes. Indeed, the L-type calcium current is larger in the soma of dopamine neurons of the SNc, leading to a higher charge transfer through L-type channels during pacemaking and bursting. Therefore, these neurons may be physiologically exposed to a larger stress than their neighbors from the VTA.
位于腹侧中脑的多巴胺能（DA）神经元持续产生缓慢的内源性起搏活动，其机制仍存在争议。有人提出，在黑质致密部（SNc），起搏更多地依赖于Ca(2+)通道，并且这些DA神经元中L型Ca(2+)通道的密度高于位于腹侧被盖区（VTA）的DA神经元。这可能导致SNc DA神经元中Ca(2+)负荷更高，并解释了它们对退化的更高易感性。然而，这一假设缺乏直接证据。我们发现，大鼠SNc DA神经元胞体中的L型电流和通道密度确实更高，并且该电流在该区域的失活较少。非平稳波动分析测量表明，SNc DA神经元胞体中的L型通道数量多得多，并且单通道电导较小，这表明这两个区域的DA神经元中L型通道可能具有不同的分子特性。由此产生的一个主要后果是，与VTA的对应神经元相比，SNc DA神经元的起搏，甚至更明显的是爆发，与通过L型通道进入的Ca(2+)增加有关。我们的结果揭示了中脑DA神经元的两个群体之间的分子和功能差异，这可能导致它们对神经退行性变的不同敏感性。
黑质致密部（SNc）和腹侧被盖区（VTA）的多巴胺神经元分别参与各种脑功能，如运动发起和目标导向行为。这项研究表明，尽管这两种神经元都以类似的规则和缓慢的起搏模式放电，但这种放电活动由不同的钙通道情况所支持。实际上，SNc多巴胺神经元胞体中的L型钙电流更大，导致在起搏和爆发期间通过L型通道的电荷转移更高。因此，这些神经元在生理上可能比来自VTA的相邻神经元面临更大的压力。
