Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease

Publication date: Available online 16 July 2019Source: NeuronAuthor(s): Jonathan W. McKinley, Ziqing Shi, Ivana Kawikova, Matthew Hur, Ian J. Bamford, Suma Priya Sudarsana Devi, Annie Vahedipour, Martin Darvas, Nigel S. BamfordSummaryMotor 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 Slc6a3DTR/+ 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 AbstractGraphical Abstract

Source: Neuron - July 18, 2019 Category: Neuroscience Source Type: research