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

Abstract

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.

D1/D5 Inverse Agonists Restore Striatal Cholinergic Interneuron Physiology in Dyskinetic Mice

“…However, acute pharmacological blockade of DA receptors does not trigger a hyperexcitability/burst‐pause phenotype in SCIN from control animals 13 . A recent study shows that sonic hedgehog (Shh) release by DAN regulates SCIN function through the activation of the G protein‐coupled receptor (GPCR) Smoothened, which activates Gαi and other signaling cascades in SCIN 10 . Smoothened agonists reduce LID while conditioned ablation of either Smoothened from SCIN or Shh from DAN promotes LID 10 .…”

“…A recent study shows that sonic hedgehog (Shh) release by DAN regulates SCIN function through the activation of the G protein‐coupled receptor (GPCR) Smoothened, which activates Gαi and other signaling cascades in SCIN 10 . Smoothened agonists reduce LID while conditioned ablation of either Smoothened from SCIN or Shh from DAN promotes LID 10 . Thus, in PD, SCIN are chronically deprived of two endogenous inhibitory regulators of AC: DA stimulation of D2R and Shh stimulation of Smoothened, which could trigger adaptive mechanisms in cAMP‐dependent pathways.…”

“…3 Striatal acetylcholine (ACh) plays a key role in PD symptoms 4,5 and recent studies involve striatal cholinergic interneurons (SCIN) in LID. [6][7][8][9][10] However, the mechanisms through which chronic DA neurons (DAN) degeneration and L-dopa therapy alter SCIN function remain poorly understood.…”

Retrospective Multicenter Study on Outcome Measurement for Dyskinesia Improvement in Parkinson’s Disease Patients with Pallidal and Subthalamic Nucleus Deep Brain Stimulation

“…DBS has been reported to be used to treat several neurobehavioral disorders such as chronic pain, major depression, Tourette’s Syndrome, addiction, obsessive–compulsive disorder and epilepsy, etc., and is mainly applied to patients with PD symptoms. Although, up to now, its potential molecular and physiological mechanism is still unknown, it has been reported that DBS may act via a few mechanisms including the electrical and neurochemical effects of stimulation in the network, the modulation of oscillatory activity and synaptic plasticity, and, potentially, neuroprotection and neurogenesis, either directly, or by modulating the circuitry or signaling pathways [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. LID remains a significant problem in patients with PD, which has a significant negative impact on health-related quality of life and health economic outcomes [ 29 ].…”

Intercellular Communication in the Central Nervous System as Deduced by Chemical Neuroanatomy and Quantitative Analysis of Images: Impact on Neuropharmacology

“…Serotonin neurons, indeed, are able to convert exogenous L-dopa into DA and release it as a “false cotransmitter” in a non-physiological “dysregulated” manner. More recently, a role for a true cotransmitter located in mesencephalic dopaminergic neurons has been described [ 166 ]. It indicated 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 and that pharmacologically 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.…”