Purkinje cell misfiring generates high-amplitude action tremors that are corrected by cerebellar deep brain stimulation

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Abstract

Tremor is currently ranked as the most common movement disorder. The brain regions and neural signals that initiate the debilitating shakiness of different body parts remain unclear. Here, we found that genetically silencing cerebellar Purkinje cell output blocked tremor in mice that were given the tremorgenic drug harmaline. We show in awake behaving mice that the onset of tremor is coincident with rhythmic Purkinje cell firing, which alters the activity of their target cerebellar nuclei cells. We mimic the tremorgenic action of the drug with optogenetics and present evidence that highly patterned Purkinje cell activity drives a powerful tremor in otherwise normal mice. Modulating the altered activity with deep brain stimulation directed to the Purkinje cell output in the cerebellar nuclei reduced tremor in freely moving mice. Together, the data implicate Purkinje cell connectivity as a neural substrate for tremor and a gateway for signals that mediate the disease.

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Author and article information

Contributors

Roy V Sillitoe:

ORCID: https://orcid.org/0000-0002-6177-6190

Richard B Ivry: Role: Senior Editor

Megan R Carey: Role: Reviewing Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 17 March 2020

Publication date Collection: 2020

Volume: 9

Electronic Location Identifier: e51928

Affiliations

[1 ]Department of Pathology and Immunology, Baylor College of Medicine HoustonUnited States

[2 ]Department of Neuroscience, Baylor College of Medicine HoustonUnited States

[3 ]Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital HoustonUnited States

[4 ]Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine HoustonUnited States

University of California, Berkeley United States

Champalimaud Foundation Portugal

Erasmus MC Netherlands

Author information

Amanda M Brown https://orcid.org/0000-0002-1484-8972

Meike E van der Heijden http://orcid.org/0000-0003-0801-8806

Joy Zhou http://orcid.org/0000-0003-1731-8800

Roy V Sillitoe https://orcid.org/0000-0002-6177-6190

Article

Publisher ID: 51928

DOI: 10.7554/eLife.51928

PMC ID: 7077982

PubMed ID: 32180549

SO-VID: bcb0aa97-7707-4fd0-af8d-6b2fc5bddde3

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 17 September 2019

Date accepted : 26 February 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: F31NS101891

Award Recipient : Amanda M Brown

Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: F31NS092264

Award Recipient : Joshua J White

Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;

Award ID: R01NS089664