Spinal astroglial cannabinoid receptors control pathological tremor
Nat Neurosci. 2021-03-18; :
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Carlsen EMM(1), Falk S(1)(2), Skupio U(3)(4), Robin L(3)(4), Zottola ACP(3)(4), Marsicano G(3)(4), Perrier JF(5).
(1)Department of Neuroscience, Faculty of Health and Medical Sciences, Universityof Copenhagen, Copenhagen, Denmark.
(2)Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
(3)U1215 INSERM, NeuroCentre Magendie, Bordeaux, France.
(4)University of Bordeaux, Bordeaux, France.
(5)Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. .
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.