Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure.
J. Clin. Invest.. 2013-06-24; 123(7): 2816-2831
DOI: 10.1172/jci67569
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1. 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.
Cutando L(1), Busquets-Garcia A, Puighermanal E, Gomis-González M, Delgado-García
JM, Gruart A, Maldonado R, Ozaita A.
Author information:
(1)Laboratori de Neurofarmacologia, Facultat de Ciències de Salut i de Vida,
Universitat Pompeu Fabra, Barcelona, Spain.
Comment in
J Clin Invest. 2013 Aug;123(8):3208-10.
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THC-withdrawn mice.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.
DOI: 10.1172/JCI67569
PMCID: PMC3696568
PMID: 23934130 [Indexed for MEDLINE]