Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

• Published in: The Journal of clinical investigation 2013-07, Vol.123 (7), p.2816-2831
• Main Authors: Cutando, Laura, Busquets-Garcia, Arnau, Puighermanal, Emma, Gomis-González, Maria, Delgado-García, José María, Gruart, Agnès, Maldonado, Rafael, Ozaita, Andrés
• Format: Article
• Language: English
• Subjects: Acquisitions & mergers; Animals; Biomedical research; Brain diseases; Cannabinoid CB2 receptors; Cannabinoid Receptor Agonists - toxicity; Cannabinoides; Cannabis; CD11b Antigen - genetics; CD11b Antigen - metabolism; Cerebellar Diseases - chemically induced; Cerebellar Diseases - immunology; Cerebellum - metabolism; Cerebellum - pathology; Cervell; Conditioning, Eyelid - drug effects; Dronabinol - toxicity; Drug abuse; Gene Expression - drug effects; Gene Expression Regulation; Health aspects; Inflammation Mediators - metabolism; Interleukin 1 Receptor Antagonist Protein - physiology; Interleukin-1beta - metabolism; Laboratory animals; Malalties; Male; Marijuana; Mice; Mice, Inbred C57BL; Microglia - drug effects; Microglia - immunology; Motor ability; Psychomotor Performance - drug effects; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - genetics; Receptor, Cannabinoid, CB2 - metabolism; Receptors; Risk factors; Rodents
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci67569

Chronic cannabis exposure can lead to cerebellar dysfunction in humans, but the neurobiological mechanisms involved remain incompletely understood. Here, we found that in mice, subchronic administration of the psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), activated cerebellar microglia and increased the expression of neuroinflammatory markers, including IL-1β. This neuroinflammatory phenotype correlated with deficits in cerebellar conditioned learning and fine motor coordination. The neuroinflammatory phenotype was readily detectable in the cerebellum of mice with global loss of the CB1 cannabinoid receptor (CB1R, Cb1(-/-) mice) and in mice lacking CB1R in the cerebellar parallel fibers, suggesting that CB1R downregulation in the cerebellar molecular layer plays a key role in THC-induced cerebellar deficits. Expression of CB2 cannabinoid receptor (CB2R) and Il1b mRNA was increased under neuroinflammatory conditions in activated CD11b-positive microglial cells. Furthermore, administration of the immunosuppressant minocycline or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1(-/-) and THC-withdrawn mice. Our results suggest that cerebellar microglial activation plays a crucial role in the cerebellar deficits induced by repeated cannabis exposure.