Date of Degree
Un Jung Kang
Animal Experimentation and Research | Behavioral Neurobiology | Neurosciences | Pharmacology
Dopamine, Basal ganglia, Parkinson's Disease, L-dopa induced dyskinesia, Sonic hedgehog, Cholinergic interneurons
Many types of neurons act as multimodal signaling centers. Yet, we have only limited insight into the regulation and functional consequences of neuronal co-transmission. For example, dopamine (DA) neurons, whose degeneration causes motor deficits characteristic of Parkinson’s Diseases (PD), communicate with all their targets by DA but only a selective subset of their targets using GABA, Glutamate, and the secreted cell signaling protein Sonic Hedgehog (Shh). It is unknown whether Levo-dopamine (L-Dopa) induced dyskinesia (LIDs), a severely debilitating side effect of DA supplementation in PD, might appear because DA neuron targets are exposed to high DA- but low Shh- signaling in medicated patients. Here I show that restoring the balance of DA and Shh signaling attenuates LID formation and acute expression in mouse and macaque models of PD. Cholinergic neurons are responsive to Shh signaling via stimulation of the Shh effector GPCR smoothened. Using conditional KO mice of pre or postsynaptic Shh we show that reduced signaling in cholinergic neurons is sufficient and necessary for LID formation. Conversely, selective expression of a constitutive active form of Smo (SmoM2) in cholinergic neurons is sufficient to render the sensitized aphakia model resistant to LID. The relative degree of imbalance of DA and Shh signaling rather than their absolute strength determines the severity of LID and highlights the bidirectional effect both factors have on LIDs. Activation of Smo reduces MAP-kinase pathway signaling, a physiological marker of LID, selectively in CINs of the dorsolateral but not dorsomedial striatum and enhances the neuronal activity marker p-rpS6240/244 through activation of Smo on CINs. Additionally, semi-chronic, pulsatile optogenetic stimulation of DA neurons results in LID-like behaviors that can be attenuated by Smo activation. Together, my data reveal that balanced Shh and DA signaling is a critical modulator of cholinergic physiology and provide an unexpected link between LID and DA neuron degeneration. Furthermore, since pulsatile L-Dopa dosing might induce a perversion in the DA neuron provided teaching signal resulting in acquisition and selection of un-purposeful, abnormal motor programs seen in LIDs, then the novel animal models described here could be a starting point for in vivo analysis to assess the function and importance of neuronal co-transmission of Shh signaling.
Malave, Lauren, "Activation of the Sonic Hedgehog Effector Smoothened Counteracts L-Dopa Induced Dyskinesia by Restoring Cholinergic Interneuron Function" (2020). CUNY Academic Works.