Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

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• dc.contributor.author Cutando Ruiz, Laura, 1985-ca
• dc.contributor.author Busquets Garcia, Arnau, 1985-ca
• dc.contributor.author Puighermanal Puigvert, Emma, 1983-ca
• dc.contributor.author Gomis González, Maria, 1988-ca
• dc.contributor.author Delgado García, José Maríaca
• dc.contributor.author Gruart, Agnèsca
• dc.contributor.author Maldonado, Rafael, 1961-ca
• dc.contributor.author Ozaita Mintegui, Andrés, 1969-ca
• dc.date.accessioned 2015-03-23T08:49:07Z
• dc.date.available 2015-03-23T08:49:07Z
• dc.date.issued 2013ca
• dc.description.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or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1(-/-) and THC-withdrawn mice.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.
• dc.description.sponsorship This study was supported by grants from the Ministerio de Ciencia e Innovación (BFU2008-03390, to A. Gruart; BFU2008-00899, to J.M. Delgado-García; SAF2007-64062 and SAF2011-29864, to R. Maldonado; and SAF2009-07309 and BFU2012-33500, to A. Ozaita); the European Commission (PHECOMP, LSHM-CT-2007-037669, to R. Maldonado); the Instituto de Salud Carlos III (RTA-RETICS, RD06/001/001, to R. Maldonado); the Generalitat de Catalunya (SGR2009-SGR00731, to R. Maldonado); the Fundació La Marató de TV3 (090910, to A. Ozaita); and the ICREA Academia (to R. Maldonado). Partial support from the EU FEDER funds is also acknowledged.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Cutando L, Busquets-Garcia A, Puighermanal E, Gomis-González M, Delgado-García JM, Gruart A et al. Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure. J Clin Invest. 2013;123(7):2816-31. DOI: 10.1172/JCI67569ca
• dc.identifier.doi http://dx.doi.org/10.1172/JCI67569
• dc.identifier.issn 0021-9738ca
• dc.identifier.uri http://hdl.handle.net/10230/23252
• dc.language.iso engca
• dc.publisher American Society for Clinical Investigationca
• dc.relation.ispartof Journal of clinical investigation. 2013;123(7):2816-31
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2008-03390
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2008-00899
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/SAF2007-64062
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-29864
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2009-07309
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2012-33500
• dc.relation.projectID info:eu-repo/grantAgreement/EC/ERC/037669
• dc.rights © American Society for Clinical Investigationca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Cannabinoides -- Receptors
• dc.subject.other Cervell--Malalties
• dc.subject.other Cannabis
• dc.title Microglial activation underlies cerebellar deficits produced by repeated cannabis exposureca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca