Dopamine 2 receptor ablation from cholinergic neurons attenuates L-DOPA induced dyskinesias

Striatal cholinergic interneurons (CIN) have been implicated in both, the facilitation as well as the attenuation of L-DOPA-induced dyskinesias (LID). These findings indicate that CIN impinge on formation and expression of LID in a dopamine state dependent manner since LID formation requires prominent oscillations of dopamine at timescales of hours over several years. However, how CIN sense and interpret striatal dopamine levels is not completely understood. CIN express both inhibitory, high affinity, Gαi coupled D2 (D2R)- and facilitatory, medium affinity, Gαs coupled D5 (D5R)-dopamine receptors. While the systemic ablation of D5R exacerbates LID, the contribution of D2R expression in CIN to LID has not been studied. Here, we produced mice with conditional ablation of D2R from choline acetyltransferase–expressing cells (D2 _ChAT KO) subjected to unilateral 6-hydroxydopamine lesions and chronic L-DOPA dosing. Behavioral assessments revealed that D2 _ChAT KO mice exhibited attenuated LID across escalating L-DOPA doses. Postmortem analyses showed reduced expression of the LID-associated marker p-ERK in CIN in the dorsolateral striatum. Further, quantification of the CIN activity marker p-rpS6 ^240/244 of mice in the L-DOPA ON and OFF state revealed that L-DOPA resulted in an increase of cholinergic activity driven by a subset of mainly dorso-laterally located CIN. D2R ablation from CIN prevented the L-DOPA associated increase in cholinergic activity. Together, these findings indicate that D2R signaling in CIN promotes LID formation, and they highlight CIN D2R as a potential molecular target for mitigating dyskinesias while preserving the therapeutic efficacy of L-DOPA. We discuss our results in the context of recently refined models how CIN contribute to aberrant plasticity in the basal ganglia of mouse models of Parkinson’s Disease.