Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure.
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or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1(-/-) and THC-withdrawn mice.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.
Laboratori de Neurofarmacologia, Facultat de Ciències de Salut i de Vida, Universitat Pompeu Fabra, Barcelona, Spain.
Laura
L
Cutando
Arnau
A
Busquets-Garcia
Emma
E
Puighermanal
Maria
M
Gomis-González
José María
JM
Delgado-García
Agnès
A
Gruart
Rafael
R
Maldonado
Andrés
A
Ozaita
D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000633:toxicity*; D002526:Cerebellar Diseases / Q000139:chemically induced* / Q000276:immunology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D003215:Conditioning, Eyelid / Q000187:drug effects; D013759:Dronabinol / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000502:physiology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology*; D011597:Psychomotor Performance / Q000187:drug effects; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism
D039481:CD11b Antigen; D063386:Cannabinoid Receptor Agonists; C507764:Il1rn protein, mouse; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol