Levodopa Causes Striatal Cholinergic Interneuron Burst‐Pause Activity in Parkinsonian Mice

Background Enhanced striatal cholinergic interneuron activity contributes to the striatal hypercholinergic state in Parkinson's disease (PD) and to levodopa‐induced dyskinesia. In severe PD, dyskinesia and motor fluctuations become seriously debilitating, and the therapeutic strategies become scarce. Given that the systemic administration of anticholinergics can exacerbate extrastriatal‐related symptoms, targeting cholinergic interneurons is a promising therapeutic alternative. Therefore, unraveling the mechanisms causing pathological cholinergic interneuron activity in severe PD with motor fluctuations and dyskinesia may provide new molecular therapeutic targets. Methods We used ex vivo electrophysiological recordings combined with pharmacological and morphological studies to investigate the intrinsic alterations of cholinergic interneurons in the 6‐hydroxydopamine mouse model of PD treated with levodopa. Results Cholinergic interneurons exhibit pathological burst‐pause activity in the parkinsonian “off levodopa” state. This is mediated by a persistent ligand‐independent activity of dopamine D1/D5 receptor signaling, involving a cyclic adenosine monophosphate (cAMP) pathway. Dysregulation of membrane ion channels that results in increased inward‐rectifier potassium type 2 (Kir2) and decreased leak currents causes the burst pause activity, which can be dampened by pharmacological inhibition of intracellular cAMP. A single challenge with a dyskinetogenic dose of levodopa is sufficient to induce persistent cholinergic interneuron burst‐pause firing. Conclusion Our data unravel a mechanism causing aberrant cholinergic interneuron burst‐pause activity in parkinsonian mice treated with levodopa. Targeting D5‐cAMP signaling and the regulation of Kir2 and leak channels may alleviate parkinsonism and dyskinesia by restoring normal cholinergic interneuron function. © 2021 International Parkinson and Movement Disorder Society