Beaver Megan L, Evans Rebekah C
Departments of Pharmacology & Physiology, Georgetown University Medical Center, Washington, DC 20007.
Neuroscience, Georgetown University Medical Center, Washington, DC 20007.
J Neurosci. 2025 Apr 16;45(16):e1443242025. doi: 10.1523/JNEUROSCI.1443-24.2025.
Dopaminergic subpopulations of the substantia nigra pars compacta (SNc) differentially degenerate in Parkinson's disease and are characterized by unique electrophysiological properties. The vulnerable population expresses a T-type calcium channel-mediated afterdepolarization (ADP) and shows rebound activity upon release from inhibition, whereas the resilient population does not have an ADP and is slower to fire after hyperpolarization. This rebound activity can trigger dopamine release in the striatum, an important component of basal ganglia function. Using whole-cell patch-clamp electrophysiology on ex vivo slices from adult mice of both sexes, we find that muscarinic activation with the nonselective muscarinic agonist oxotremorine inhibits rebound activity more strongly in vulnerable versus resilient SNc neurons. Here, we show that this effect depends on the direct activation of muscarinic receptors on the SNc dopaminergic neurons. Through a series of pharmacological and transgenic knock-out experiments, we tested whether the muscarinic inhibition of rebound was mediated through the canonical rebound-related ion channels: T-type calcium channels, hyperpolarization-activated cation channels (HCN), and A-type potassium channels. We find that muscarinic receptor activation inhibits HCN-mediated current ( ) in vulnerable SNc neurons but that activity is not necessary for the muscarinic inhibition of rebound activity. Similarly, we find that oxotremorine inhibits rebound activity independently of T-type calcium channels and A-type potassium channels. Together these findings reveal new principles governing acetylcholine and dopamine interactions, showing that muscarinic receptors directly affect SNc rebound activity in the midbrain at the somatodendritic level and differentially modify information processing in distinct SNc subpopulations.
黑质致密部（SNc）的多巴胺能亚群在帕金森病中会发生不同程度的退化，并具有独特的电生理特性。易损亚群表达一种由T型钙通道介导的去极化后电位（ADP），在解除抑制后表现出反弹活动，而有韧性的亚群则没有ADP，在超极化后放电较慢。这种反弹活动可触发纹状体中的多巴胺释放，而纹状体是基底神经节功能的重要组成部分。通过对成年雌雄小鼠的离体脑片进行全细胞膜片钳电生理实验，我们发现，使用非选择性毒蕈碱激动剂氧化震颤素激活毒蕈碱受体，在易损的SNc神经元中比在有韧性的SNc神经元中更强烈地抑制反弹活动。在此，我们表明这种效应取决于SNc多巴胺能神经元上毒蕈碱受体的直接激活。通过一系列药理学和转基因敲除实验，我们测试了毒蕈碱对反弹的抑制是否通过与反弹相关的经典离子通道介导：T型钙通道、超极化激活阳离子通道（HCN）和A型钾通道。我们发现毒蕈碱受体激活抑制了易损SNc神经元中HCN介导的电流（ ），但 活动对于毒蕈碱对反弹活动的抑制并非必需。同样，我们发现氧化震颤素独立于T型钙通道和A型钾通道抑制反弹活动。这些发现共同揭示了支配乙酰胆碱和多巴胺相互作用的新原理，表明毒蕈碱受体在树突体水平直接影响中脑SNc的反弹活动，并在不同的SNc亚群中差异性地改变信息处理。
