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J Clin Invest. 2013 Jul;123(7):2816-31. doi: 10.1172/JCI67569. Epub 2013 Jun 24.

Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure.

Author information

1
Laboratori de Neurofarmacologia, Facultat de Ciències de Salut i de Vida, Universitat Pompeu Fabra, Barcelona, Spain.

Abstract

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or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1(-/-) and THC-withdrawn mice.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.

PMID:
23934130
PMCID:
PMC3696568
DOI:
10.1172/JCI67569
[Indexed for MEDLINE]
Free PMC Article

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