Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Pharmacology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA.
Neuron. 2021 Apr 7;109(7):1137-1149.e5. doi: 10.1016/j.neuron.2021.01.028. Epub 2021 Feb 17.
Progressive loss of dopamine inputs in Parkinson's disease leads to imbalances in coordinated signaling of dopamine and acetylcholine (ACh) in the striatum, which is thought to contribute to parkinsonian motor symptoms. As reciprocal interactions between dopamine inputs and cholinergic interneurons (ChIs) control striatal dopamine and ACh transmission, we examined how partial dopamine depletion in an early-stage mouse model for Parkinson's disease alters nigral regulation of cholinergic activity. We found region-specific alterations in how remaining dopamine inputs regulate cholinergic excitability that differ between the dorsomedial (DMS) and dorsolateral (DLS) striatum. Specifically, we found that dopamine depletion downregulates metabotropic glutamate receptors (mGluR1) on DLS ChIs at synapses where dopamine inputs co-release glutamate, abolishing the ability of dopamine inputs to drive burst firing. This loss underlies parkinsonian motor impairments, as viral rescue of mGluR1 signaling in DLS ChIs was sufficient to restore circuit function and attenuate motor deficits in early-stage parkinsonian mice.
帕金森病中多巴胺输入的逐渐丧失导致纹状体中多巴胺和乙酰胆碱（ACh）的协调信号失衡，这被认为是导致帕金森运动症状的原因。由于多巴胺输入和胆碱能中间神经元（ChIs）之间的相互作用控制着纹状体中的多巴胺和 ACh 传递，我们研究了帕金森病早期小鼠模型中多巴胺的部分耗竭如何改变黑质对胆碱能活性的调节。我们发现，剩余的多巴胺输入调节背侧纹状体（DMS）和背外侧纹状体（DLS）中胆碱能兴奋性的区域特异性改变存在差异。具体而言，我们发现多巴胺耗竭下调了 DLS ChIs 上多巴胺输入共释放谷氨酸的突触处的代谢型谷氨酸受体（mGluR1），从而消除了多巴胺输入驱动爆发式放电的能力。这种丧失是帕金森运动障碍的基础，因为 DLS ChIs 中的 mGluR1 信号的病毒挽救足以恢复回路功能并减轻早期帕金森病小鼠的运动缺陷。
