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

Background: 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. Method: 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. Results: 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. Conclusion: The activation of D2 specifically on CIN is a key driver of LID.

Dopaminergic co-transmission with sonic hedgehog inhibits abnormal involuntary movements in models of Parkinson's disease and L-Dopa induced dyskinesia.

L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinson's Disease. The mechanistic underpinnings of LID remain obscure. Here we report that diminished sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons facilitates the formation and expression of LID. We find that the pharmacological activation of Smoothened, a downstream effector of Shh, attenuates LID in the neurotoxic 6-OHDA- and genetic aphakia mouse models of Parkinson's Disease. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from dopamine neurons or Smoothened activity in cholinergic interneurons promotes LID. Conversely, the selective expression of constitutively active Smoothened in cholinergic interneurons is sufficient to render the sensitized aphakia model of Parkinson's Disease resistant to LID. Furthermore, acute depletion of Shh from dopamine neurons through prolonged optogenetic stimulation in otherwise intact mice and in the absence of L-Dopa produces LID-like involuntary movements. These findings indicate that augmenting Shh signaling in the L-Dopa treated brain may be a promising therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa.