Neurophysiology of Brain Circuits Team, Institut de biologie de l'Ecole normale supérieure (IBENS), Ecole normale supérieure, CNRS, INSERM, PSL Research University, 75005, Paris, France.
Center for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, Université PSL, Paris, France.
Nat Commun. 2022 Jun 9;13(1):3211. doi: 10.1038/s41467-022-30844-0.
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.
慢性左旋多巴治疗是帕金森病（PD）的金标准治疗方法，但会导致不自主运动的出现，称为左旋多巴诱导的运动障碍（LID）。小脑刺激已被证明可以降低 PD 患者的 LID 严重程度。在这里，为了确定小脑刺激如何诱导 LID 缓解，我们在自由活动的 LID 小鼠中进行了每日短暂的浦肯野细胞（PC）光遗传学刺激。我们证明这些刺激足以抑制 LID，甚至可以预防其发展。这种症状缓解伴随着小脑核、运动皮层和旁正中丘脑异常神经元放电的正常化。小脑脚-旁正中束通路的抑制抵消了小脑刺激的有益效果。此外，小脑刺激逆转了 D1 纹状体神经元的可塑性，并使转录因子 FosB 的过度表达正常化，FosB 是与 LID 因果相关的转录因子。这些发现表明，每日 PC 刺激可以缓解和预防 LID，恢复广泛的运动网络功能，可能对 LID 治疗有价值。
