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or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1–/– and THC-withdrawn mice.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

×

Figure 6

Acute IL-1RA administration resolves the cerebellar deficit resulting from cannabinoid receptor deregulation and neuroinflammation.

Options: View larger image (or click on image) Download as PowerPoint
Acute IL-1RA administration resolves the cerebellar deficit resulting fr...
(A) Percentage of conditioned eyelid responses collected from mice subchronically treated with THC (5 and 20 mg/kg) and VEH (n = 5–10 mice per group). See Supplemental Figure 1C for experimental chronogram. *P < 0.05, **P < 0.01, ***P < 0.001 versus subchronic VEH treatment plus DMSO; #P < 0.05, ##P < 0.01, ###P < 0.001 versus subchronic THC (5 or 20 mg/kg) treatment plus DMSO. (B) Percentage of conditioned eyelid responses collected from WT and Cb1–/– mice (n = 5–10 per group). See Supplemental Figure 12B for experimental chronogram. *P < 0.05, **P < 0.01 versus WT plus DMSO; #P < 0.05, ##P < 0.01, ###P < 0.001 versus Cb1–/– plus DMSO. (C) Motor coordination analysis with the coat-hanger test in subchronic THC (5 and 20 mg/kg) and subchronic VEH conditions 5 days after spontaneous withdrawal (n = 9–15 mice per group). Four hours before the test, mice received an acute injection of IL-1RA (100 mg/kg, i.p.) or its VEH (DMSO). *P < 0.05, **P < 0.01 versus subchronic VEH. (D) Motor coordination analysis with the coat-hanger test in WT and Cb1–/– mice (n = 8–13 per group). Four hours before the test, mice received an injection of IL-1RA or its VEH. **P < 0.001 versus WT plus DMSO; ##P < 0.01 versus Cb1–/– plus DMSO.