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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Bérénice Coutant & Jimena Laura Frontera & Elodie Perrin & Adèle Combes & Thibault Tarpin & Fabien Menardy & Caroline Mailhes-Hamon & Sylvie Perez & Bertrand Degos & Laurent Venance & Clément Léna & D, 2022. "Cerebellar stimulation prevents Levodopa-induced dyskinesia in mice and normalizes activity in a motor network," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30844-0
    DOI: 10.1038/s41467-022-30844-0
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    References listed on IDEAS

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    1. Jones G. Parker & Jesse D. Marshall & Biafra Ahanonu & Yu-Wei Wu & Tony Hyun Kim & Benjamin F. Grewe & Yanping Zhang & Jin Zhong Li & Jun B. Ding & Michael D. Ehlers & Mark J. Schnitzer, 2018. "Diametric neural ensemble dynamics in parkinsonian and dyskinetic states," Nature, Nature, vol. 557(7704), pages 177-182, May.
    2. Sébastien Valverde & Marie Vandecasteele & Charlotte Piette & Willy Derousseaux & Giuseppe Gangarossa & Asier Aristieta Arbelaiz & Jonathan Touboul & Bertrand Degos & Laurent Venance, 2020. "Deep brain stimulation-guided optogenetic rescue of parkinsonian symptoms," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    3. Lauren N. Miterko & Tao Lin & Joy Zhou & Meike E. Heijden & Jaclyn Beckinghausen & Joshua J. White & Roy V. Sillitoe, 2021. "Neuromodulation of the cerebellum rescues movement in a mouse model of ataxia," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Le Xiao & Caroline Bornmann & Laetitia Hatstatt-Burklé & Peter Scheiffele, 2018. "Regulation of striatal cells and goal-directed behavior by cerebellar outputs," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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