Department of Pediatrics, Yale University, New Haven, CT 06510, USA.
Department of Pathology, University of Washington, Seattle, WA 98105, USA.
Neuron. 2019 Sep 25;103(6):1056-1072.e6. doi: 10.1016/j.neuron.2019.06.013. Epub 2019 Jul 16.
Motor and cognitive functions depend on the coordinated interactions between dopamine (DA) and acetylcholine (ACh) at striatal synapses. Increased ACh availability was assumed to accompany DA deficiency based on the outcome of pharmacological treatments and measurements in animals that were critically depleted of DA. Using Slc6a3 diphtheria-toxin-sensitive mice, we demonstrate that a progressive and L-dopa-responsive DA deficiency reduces ACh availability and the transcription of hyperpolarization-activated cation (HCN) channels that encode the spike timing of ACh-releasing tonically active striatal interneurons (ChIs). Although the production and release of ACh and DA are reduced, the preponderance of ACh over DA contributes to the motor deficit. The increase in striatal ACh relative to DA is heightened via D1-type DA receptors that activate ChIs in response to DA release from residual axons. These results suggest that stabilizing the expression of HCN channels may improve ACh-DA reciprocity and motor function in Parkinson's disease (PD). VIDEO ABSTRACT.
运动和认知功能依赖于纹状体突触处多巴胺 (DA) 和乙酰胆碱 (ACh) 的协调相互作用。根据药物治疗的结果以及对 DA 严重耗竭的动物的测量，人们认为 ACh 的可用性增加伴随着 DA 缺乏。利用 Slc6a3 白喉毒素敏感小鼠，我们证明进行性且对 L-多巴有反应的 DA 缺乏会降低 ACh 的可用性以及编码释放 ACh 的紧张性活跃纹状体中间神经元 (ChIs) 的尖峰定时的超极化激活阳离子 (HCN) 通道的转录。尽管 ACh 和 DA 的产生和释放减少，但 ACh 对 DA 的优势导致运动缺陷。通过 D1 型 DA 受体增加纹状体中的 ACh 与 DA 的比值，这些受体响应残留轴突中 DA 的释放而激活 ChIs。这些结果表明，稳定 HCN 通道的表达可能会改善帕金森病 (PD) 中的 ACh-DA 相互作用和运动功能。视频摘要。
