Fig. 8. Manipulation of Shh signaling between DAN and CIN modulates LID, pERK, and p-rpS6 across multiple paradigms spanning time scales and degrees of DAN denervation.

a–d Across the animal models of Parkinson’s Disease and experimental paradigms utilized in this study, a relative imbalance between Shh (low) and DA (high) signaling onto CIN was consistently observed to induce LID-like pathology. This pathology was accompanied by decreases in neuronal activity marker p-rpS6 and increases in LID histological marker pERK among CIN of the DLS. States defined by relatively low Shh and high DA signaling onto CIN facilitated LID. Postsynaptic manipulations of Smo on CIN produced effects mimicking the complementary pharmacological and presynaptic manipulations suggesting CIN are the relevant cell type through which Shh-dependent modulation of LID occurs. DAN are the physiological source of Shh on which CIN depend and ablation of Shh from DAN produced LID-like behavior and changes in CIN pERK and p-rpS6 levels. Further, not only was acute Smo pharmacology sufficient to rapidly attenuate LID following SAG administration, but prolonged optogenetic stimulation of DAN led to a diminishment of Shh signaling within the course of a single hour and produced behavior resembling that observed in LID. Thus the relative balance between DA and Shh signaling onto CIN is not only perturbed following drastic denervation of DAN, but can vary at shorter time scales. e The findings derived from these distinct paradigms indicates that the Shh/Smo signaling pathway counteracts DA signaling in CIN. *Changes in pErk determined from examination of murine models.