Targeting the endocannabinoid system in the treatment of fragile X syndrome

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• dc.contributor.author Busquets Garcia, Arnau, 1985-ca
• dc.contributor.author Gomis González, Maria, 1988-ca
• dc.contributor.author Guegan, Thomas, 1983-ca
• dc.contributor.author Agustín Pavón, Carmenca
• dc.contributor.author Pastor, Antonioca
• dc.contributor.author Mato, Susanaca
• dc.contributor.author Pérez Samartín, A.ca
• dc.contributor.author Matute, Carlosca
• dc.contributor.author Torre Fornell, Rafael de laca
• dc.contributor.author Dierssen, Maraca
• dc.contributor.author Maldonado, Rafael, 1961-ca
• dc.contributor.author Ozaita Mintegui, Andrés, 1969-ca
• dc.date.accessioned 2015-03-30T07:21:13Z
• dc.date.available 2015-03-30T07:21:13Z
• dc.date.issued 2013ca
• dc.description.abstract Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism, is caused by the silencing of the FMR1 gene, leading to the loss of fragile X mental retardation protein (FMRP), a synaptically expressed RNA-binding protein regulating translation. The Fmr1 knockout model recapitulates the main traits of the disease. Uncontrolled activity of metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) signaling seem crucial in the pathology of this disease. The endocannabinoid system (ECS) is a key modulator of synaptic plasticity, cognitive performance, anxiety, nociception and seizure susceptibility, all of which are affected in FXS. The cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) are activated by phospholipid-derived endocannabinoids, and CB1R-driven long-term regulation of synaptic strength, as a consequence of mGluR5 activation, is altered in several brain areas of Fmr1 knockout mice. We found that CB1R blockade in male Fmr1 knockout (Fmr1(-/y)) mice through pharmacological and genetic approaches normalized cognitive impairment, nociceptive desensitization, susceptibility to audiogenic seizures, overactivated mTOR signaling and altered spine morphology, whereas pharmacological blockade of CB2R normalized anxiolytic-like behavior. Some of these traits were also reversed by pharmacological inhibition of mTOR or mGluR5. Thus, blockade of ECS is a potential therapeutic approach to normalize specific alterations in FXS.
• dc.description.sponsorship This study was supported by grants from La Marató de TV3 (#090910 to AO), Grants from the Ministerio de Ciencia e Innovación (#SAF2009-07309 to AO, #SAF2011-29864 to RM and SAF2010-21547 to CM); Instituto de Salud Carlos III (RD06/0001/0001 to RM); PLAN E (Plan Español para el Estímulo de la Economía y el Empleo); Generalitat de Catalunya (SGR-2009-00731 to RM and SGR2009-00718 to RdlT); ICREA (Institució Catalana de Recerca i Estudis Avançats)/nAcademia to RM
• dc.format.mimetype application/pdfca
• dc.identifier.citation Busquets-Garcia A, Gomis-González M, Guegan T, Agustín-Pavón C, Pastor A, Mato S et al. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat Med. 2013 May;19(5):603-7. DOI: 10.1038/nm.3127ca
• dc.identifier.doi http://dx.doi.org/10.1038/nm.3127
• dc.identifier.issn 1078-8956ca
• dc.identifier.uri http://hdl.handle.net/10230/23307
• dc.language.iso engca
• dc.publisher Nature Publishing Groupca
• dc.relation.ispartof Nature Medicine. 2013 May;19(5):603-7
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2009-07309
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-29864
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010-21547
• dc.rights © Nature Publishing Group. http://dx.doi.org/10.1038/nm.3127ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Síndrome del cromosoma X fràgil -- Metabolisme
• dc.subject.other Cannabinoides -- Metabolisme
• dc.title Targeting the endocannabinoid system in the treatment of fragile X syndromeca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/acceptedVersionca