Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure
Laura Cutando, … , Rafael Maldonado, Andrés Ozaita
Laura Cutando, … , Rafael Maldonado, Andrés Ozaita
Published June 24, 2013
Citation Information: J Clin Invest. 2013;123(7):2816-2831. https://doi.org/10.1172/JCI67569.
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Research Article

Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

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or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1–/– and THC-withdrawn mice.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

Authors

Laura Cutando, Arnau Busquets-Garcia, Emma Puighermanal, Maria Gomis-González, José María Delgado-García, Agnès Gruart, Rafael Maldonado, Andrés Ozaita

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Figure 3

MIN administration after subchronic THC exposure prevents the activation of microglia in the cerebellum.

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MIN administration after subchronic THC exposure prevents the activation...
(A) Immunoblot detection and quantification of cerebellar CD11b (n = 5 mice per group) at the end of subchronic exposure to MIN or SAL under subchronic THC (5 and 20 mg/kg) and subchronic VEH treatment conditions. (B) Morphological analysis of IBA1+ cells in the cerebellar cortex (n = 3–4 mice per group, 4–5 cells per mouse). Scale bar: 25 μm. (C) Immunoblot detection and quantification of cerebellar CB1R (n = 6 mice per group) at the end of MIN or SAL exposure under subchronic THC (5 and 20 mg/kg) and subchronic VEH treatment conditions. (D) Immunolocalization and quantification of CB1R intensity in the cerebellar molecular layer at the end of subchronic exposure to MIN or SAL under subchronic THC (5 and 20 mg/kg) and subchronic VEH treatment conditions (n = 4 mice per group; 3–4 images per mouse). Note the downregulation of CB1R in the molecular layer of the cerebellum 5 days after the end of THC-5 and THC-20 subchronic treatments. Scale bar: 75 μm. *P < 0.05; **P < 0.01; ***P < 0.001 versus subchronic VEH plus SAL (5 days); #P < 0.05; ##P < 0.01; ###P < 0.001 versus subchronic THC (5 or 20 mg/kg) plus SAL (5 days) treatment.