(P116.02) Activation of D2 receptor on cholinergic interneurons is critical for the induction of L-Dopa induced dyskinesia

Society for Neuroscience Global Connectome, 2021

Santiago Uribe-Cano, Kalena Liu, Lauren Malave, and Andreas H. Kottmann

Dopamine neuron (DAN) loss is a hallmark sign of Parkinson’s Disease (PD). L-Dopa therapy, the gold-standard treatment for PD, attenuates bradykinesia and akinesia in patients. Unfortunately, prolonged L-Dopa use eventually produces a debilitating side-effect called L-Dopa induced dyskinesia (LID) in ~90% of medicated PD patients. The mechanistic underpinnings of LID remain obscure and are of interest for the purpose of improving PD therapies. Cholinergic interneurons of the striatum (CIN) are projection targets of DAN and undergo pathophysiological changes in response to DAN degeneration. These changes to CIN physiology have been suggested key for LID formation, a contention supported by studies demonstrating that manipulations of CIN activity in animal models of LID can impact LID expression. While a link between aberrant CIN function and LID is increasingly clear, the nature of this relationship remains disputed. Namely, both increased and decreased CIN activity have been implicated in LID. Therefore, to reconcile these results, the changes to CIN physiology following DAN loss and subsequent L-Dopa treatment, as well as the mechanisms responsible for those changes, warrant closer examination.
DAN are known to signal CIN via numerous signaling factors, all of which are lost as DAN degenerate in PD. L-Dopa therapy restores dopamine (DA) signaling but fails to restore the additional signaling factors released by DAN to CIN. We recently found that release of the signaling peptide sonic hedgehog (Shh) from DAN to CIN is crucial in the prevention of aberrant CIN physiology and LID induction. Additionally, loss of Shh signaling on CIN reduces levels of neuronal activity marker p-rpS6 among dorsolateral CIN. These observations suggest that hypo-active CIN physiology may be a key driver of LID in the striatum. CIN express both inhibitory D2 receptors and facilitatory D5 receptors. Here, we further probe the degree to which CIN hypo-activity, specifically through activation of D2 following L-Dopa administration, may be responsible for LID induction. We hypothesize that reducing inhibition from D2 signaling on CIN can help maintain normal CIN physiology during L-Dopa therapy and confer LID resistance. To test this, we utilized CIN specific ablation of the D2 receptor in 6-OHDA animals treated with L-Dopa. Behavioral scoring of abnormal involuntary movements was used to quantify LID in D2 knockout and heterozygous mice. Additionally, we report differences in CIN p-rpS6 levels as well as the LID cytochemical marker p-ERK. Our initial results suggest that ablation of D2 signaling from CIN prevents the induction of LID behavior and associated changes in CIN physiology.