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Spinal astroglial cannabinoid receptors control pathological tremor

Nature Neuroscience volume 24, pages 658–666 (2021)Cite this article

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Abstract

Cannabinoids reduce tremor associated with motor disorders induced by injuries and neurodegenerative disease. Here we show that this effect is mediated by cannabinoid receptors on astrocytes in the ventral horn of the spinal cord, where alternating limb movements are initiated. We first demonstrate that tremor is reduced in a mouse model of essential tremor after intrathecal injection of the cannabinoid analog WIN55,212-2. We investigate the underlying mechanism using electrophysiological recordings in spinal cord slices and show that endocannabinoids released from depolarized interneurons activate astrocytic cannabinoid receptors, causing an increase in intracellular Ca2+, subsequent release of purines and inhibition of excitatory neurotransmission. Finally, we show that the anti-tremor action of WIN55,212-2 in the spinal cords of mice is suppressed after knocking out CB1 receptors in astrocytes. Our data suggest that cannabinoids reduce tremor via their action on spinal astrocytes.

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Fig. 1: Activation of CB receptors in the spinal cord has an anti-tremor effect.
Fig. 2: Depolarization of ventral horn interneurons induces suppression of excitatory synaptic transmission.
Fig. 3: DSE in the spinal cord occurs between interneurons.
Fig. 4: Neuronal depolarization activates astrocytic CB1 receptors.
Fig. 5: DSE in the ventral horn is mediated by astrocytes.
Fig. 6: Purines mediate suppression of excitation induced by 2-AG and depolarization.
Fig. 7: DSE occurs in the adult spinal cord but not in animals lacking astrocytic CB1 receptors.
Fig. 8: Knocking out astrocytic CB1 receptors prevents the anti-tremor effect of WIN55,212-2.

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Data availability

Electrophysiological, imaging and tremor data are available at zenodo.org; https://doi.org/10.5281/zenodo.4478494. Data for immunohistochemistry are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

Code written for data analysis of this study is available at https://github.com/perrierlab/Carlsen_et_al_2021.

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Acknowledgements

We thank F. Kirchhoff (University of Saarland) for providing the Tgn(hgFAPEGEP) mice, M. Beato (UCL) for his help with the adult spinal cord slice preparation, A. Fletcher-Jones and A. Eraso for technical support and L. Anson for helping edit the manuscript. The study was funded by the Offerfonden (to J.F.P.), the Aase og Ejnar Danielsens Fond (to E.M.C.), the Den Owensenske Fond (to J.F.P.), the Læge Sofus Carl Emil Friis og hustru Olga Doris Fond (to J.F.P.), the Danmarks Frie Forskningsfond (9039-00072B to J.F.P.), the European Research Council (grant MiCaBra, ERC-2017-AdG-786467 to G.M.), Region Nouvelle Aquitaine, Agence Nationale de la Recherche ANR, NeuroNutriSens (ANR-13-BSV4-0006 and ORUPS ANR-16-CE37-0010-01), BRAIN (ANR-10-LABX-0043, to G.M.) and the Fondation pour la Recherche Médicale (grant no. FRM SPF201809006908 to U.S.).

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Authors and Affiliations

  1. Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Eva Maria Meier Carlsen, Sarah Falk & Jean-François Perrier

  2. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Sarah Falk

  3. U1215 INSERM, NeuroCentre Magendie, Bordeaux, France

    Urszula Skupio, Laurie Robin, Antonio C. Pagano Zottola & Giovanni Marsicano

  4. University of Bordeaux, Bordeaux, France

    Urszula Skupio, Laurie Robin, Antonio C. Pagano Zottola & Giovanni Marsicano

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  1. Eva Maria Meier Carlsen
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Contributions

E.M.C. and J.F.P. designed the project. E.M.C. performed the electrophysiological and imaging experiments. S.F. and E.M.C. performed the behavioral experiments. U.S., L.R. and A.P.Z. performed the validation of the transgenic model. G.M. and J.F.P. supervised the research. E.M.C. and J.F.P. wrote the paper. All authors approved the final version.

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Correspondence to Jean-François Perrier.

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Peer review information Nature Neuroscience thanks Alexander Gourine and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Carlsen, E.M.M., Falk, S., Skupio, U. et al. Spinal astroglial cannabinoid receptors control pathological tremor. Nat Neurosci 24, 658–666 (2021). https://doi.org/10.1038/s41593-021-00818-4

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