Cerebellar stimulation prevents Levodopa-induced dyskinesia in mice and normalizes activity in a motor network

Bérénice Coutant, Jimena Laura Frontera, Elodie Perrin, Adèle Combes, Thibault Tarpin, Fabien Menardy, Caroline Mailhes-Hamon, Sylvie Perez, Bertrand Degos, Laurent Venance, Clément Léna () and Daniela Popa ()
Additional contact information
Bérénice Coutant: PSL Research University
Jimena Laura Frontera: PSL Research University
Elodie Perrin: Université PSL
Adèle Combes: PSL Research University
Thibault Tarpin: PSL Research University
Fabien Menardy: PSL Research University
Caroline Mailhes-Hamon: PSL Research University
Sylvie Perez: Université PSL
Bertrand Degos: Université PSL
Laurent Venance: Université PSL
Clément Léna: PSL Research University
Daniela Popa: PSL Research University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Chronic Levodopa therapy, the gold-standard treatment for Parkinson’s Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulation has been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulation induces LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving LID mice. We demonstrated that these stimulations are sufficient to suppress LID or even prevent their development. This symptomatic relief is accompanied by the normalization of aberrant neuronal discharge in the cerebellar nuclei, the motor cortex and the parafascicular thalamus. Inhibition of the cerebello-parafascicular pathway counteracted the beneficial effects of cerebellar stimulation. Moreover, cerebellar stimulation reversed plasticity in D1 striatal neurons and normalized the overexpression of FosB, a transcription factor causally linked to LID. These findings demonstrate LID alleviation and prevention by daily PC stimulations, which restore the function of a wide motor network, and may be valuable for LID treatment.

Date: 2022
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DOI: 10.1038/s41467-022-30844-0

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