Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

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


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or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1(-/-) and THC-withdrawn mice.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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism
  • Cannabinoid Receptor Agonists / toxicity*
  • Cerebellar Diseases / chemically induced*
  • Cerebellar Diseases / immunology
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Conditioning, Eyelid / drug effects
  • Dronabinol / toxicity*
  • Gene Expression / drug effects
  • Gene Expression Regulation
  • Inflammation Mediators / metabolism
  • Interleukin 1 Receptor Antagonist Protein / physiology
  • Interleukin-1beta / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / immunology*
  • Psychomotor Performance / drug effects
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / metabolism


  • CD11b Antigen
  • Cannabinoid Receptor Agonists
  • Il1rn protein, mouse
  • Inflammation Mediators
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Dronabinol