Spinal astroglial cannabinoid receptors control pathological tremor

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 Ca 2+ , 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 CB 1 receptors in astrocytes. Our data suggest that cannabinoids reduce tremor via their action on spinal astrocytes.Everyone experiences the involuntary, rhythmic, oscillatory movement of body parts that is known as tremor 1 . Physiological tremor is not a burden due to its modest amplitude. In contrast, pathological forms of tremor can be extremely disabling for patients 2 , and can Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Epigenetic Regulation of Cannabinoid-Mediated Attenuation of Inflammation and Its Impact on the Use of Cannabinoids to Treat Autoimmune Diseases

“…The CD200–CD200R axis enhanced by AEA is believed to shift microglial cells from an M1 to M2 phenotype, which provides neuroprotection [ 88 ]. Furthermore, CB1 agonist WIN55,212-2 induces astrocytes to release purines, which reduce tremors in an animal model of essential tremors [ 24 ].…”

“…M2 microglia are immunosuppressive cells [ 22 , 23 ]. Furthermore, endocannabinoid binding to astrocytes’ cannabinoid receptor 1 (CB1) exerts anti-tremor effects in an essential tremor animal model [ 24 ]. In contrast, some limited studies have also shown that cannabinoids can promote inflammatory cytokine production under certain conditions [ 25 , 26 ].…”

Role of astrocytes in rhythmic motor activity

“…Under pathological conditions such as multiple sclerosis, stroke, or brain injury, tremor can become disabling. In a recent study, it was shown that astrocytes located in the ventral horn of the spinal cord are important for decreasing the amplitude of tremor (Carlsen et al, 2021 ). Active spinal interneurons from the ventral horn release endocannabinoids that bind to cannabinoid receptors type 1 (CB1) expressed by neighboring astrocytes.…”

“…Thus, in contrast to neurons, information processing in astrocytes does not necessarily require somatic integration of signals. Gliotransmitters released from astrocytes include ATP, glutamate, D‐Serine, and GABA (Araque et al, 2014 ; Carlsen et al, 2021 ; Christensen et al, 2013 , 2018 ; Khakh & Sofroniew, 2015 ; Perea et al, 2009 ; Santello et al, 2019 ). Consequently, astrocytes have all the properties necessary for participating in information processing in the central nervous system and the number of studies demonstrating their importance in physiological functions is continuously growing.…”

“…Consequently, astrocytes have all the properties necessary for participating in information processing in the central nervous system and the number of studies demonstrating their importance in physiological functions is continuously growing. Here we will review the most recent articles demonstrating a role for astrocytes in the modulation and the genesis of motor rhythmic behaviors illustrated by breathing, locomotion, tremor, and mastication (Broadhead & Miles, 2020 ; Carlsen et al, 2021 ; Carlsen & Perrier, 2014 ; Christensen et al, 2013 ; Gourine et al, 2010 ; Morquette et al, 2015 ; Mu et al, 2019 ).…”