Cerebellar stimulations prevent Levodopa-induced dyskinesia in mice and normalize brain activity

Abstract

Chronic Levodopa therapy, the gold-standard treatment of Parkinsons Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulations have been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulations induce LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving 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 effect of cerebellar stimulations. Moreover, cerebellar stimulations 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 brain motor network, and may be valuable for LID treatment.