L-Dopa induced dyskinesias require Cholinergic Interneuron expression of Dopamine 2 receptor

Striatal Cholinergic Interneurons (CIN) are drivers of L-Dopa induced Dyskinesias (LID). However, what signaling pathways elicit aberrant CIN activity remains unclear. CIN express D2 and D5 receptors suggesting repeated activation of these receptors in response to L-Dopa could promote LID. While the role of D5 in this process has recently been probed, little is known about the role of D2.

Mice with CIN-specific D2 ablation (D2 _CIN KO) underwent unilateral 6-OHDA lesion and chronic L-Dopa dosing, throughout which LID severity was quantified. The effect of D2 _CIN KO on histological markers of LID severity and CIN activity were also quantified postmortem.

D2 _CIN KO attenuated LID across L-Dopa doses, reduced expression of histological LID marker p-ERK, and prevented L-Dopa-induced increases in CIN activity marker p-rpS6 in the dorsolateral striatum.

The activation of D2 specifically on CIN is a key driver of LID.