(#7156) Sonic Hedgehog Signaling onto Striatal Cholinergic Interneurons Impinges on D2 Signaling via the Integrated Stress Response Pathway to Mediate L-dopa Induced Dyskinesia Induction

Neuroscience, 2021 (SFN)

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

Dopamine neuron (DAN) loss, a hallmark sign of Parkinson’s Disease (PD), is treated with L-Dopa therapy which attenuates bradykinesia and akinesia in patients. Unfortunately, prolonged treatment with L-Dopa leads to a debilitating side effect called L-Dopa induced dyskinesia (LID) in a majority of medicated PD patients. Cholinergic interneurons of the striatum (CIN), which are projection targets of DAN and undergo pathophysiological changes in response to DAN degeneration, have been increasingly implicated in LID. However, the mechanistic underpinnings of how L-Dopa-derived Dopamine (DA) signaling onto CIN interacts with the pathophysiological changes CIN undergo following DAN degeneration to produce LID remains poorly understood.

CIN express both inhibitory D2 and facilitatory D5 receptors. In the work presented here, we probe the degree to which DA action via D2 on CIN following L-Dopa administration may be responsible for LID induction. Amazingly, selective ablation of the D2 receptor from CIN in 6-OHDA animals treated with L-Dopa attenuated LID and reduced levels of the LID cytochemical marker p-ERK among CIN. Unexpectedly however, quantification of the neuronal activity marker p-rpS6 in CIN suggested that D2 ablation leads to lower activity levels in CIN following L-Dopa administration. In parallel lines of study, 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. Prior work from our group has also demonstrated that Shh signaling onto CIN impinges on the Integrated Stress Response pathway (ISR), suggesting that changes in physiological cell stress among CIN following DAN degeneration are mediated by changes in Shh signaling. These findings are made relevant to D2 signaling on CIN given recent work by Helseth and colleagues (2021) demonstrating that attenuation of the ISR pathway in CIN can produce an inversion of D2 from acting as inhibitory to excitatory. Specifically, we hypothesize that altered ISR activity in CIN mediated by changes in Shh signaling can lead to disruptions of physiological D2 signaling and promote LID. Here, alongside our characterization of how D2 ablation from CIN prevents LID induction, we begin to investigate how Shh signaling impinges on the ISR pathway and impacts D2 signaling on CIN to prime LID formation following DAN degeneration in PD.