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Targeting the endocannabinoid system in the treatment of fragile X syndrome

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dc.contributor.author Busquets Garcia, Arnau, 1985-
dc.contributor.author Gomis González, Maria
dc.contributor.author Guegan, Thomas, 1983-
dc.contributor.author Agustín Pavón, Carmen
dc.contributor.author Pastor, Antonio
dc.contributor.author Mato, Susana
dc.contributor.author Pérez Samartín, A.
dc.contributor.author Matute, Carlos
dc.contributor.author Torre Fornell, Rafael de la
dc.contributor.author Dierssen, Mara
dc.contributor.author Maldonado, Rafael, 1961-
dc.contributor.author Ozaita Mintegui, Andrés, 1969-
dc.date.accessioned 2015-03-30T07:21:13Z
dc.date.available 2015-03-30T07:21:13Z
dc.date.issued 2013
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.3127
dc.identifier.issn 1078-8956
dc.identifier.uri http://hdl.handle.net/10230/23307
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/pdf
dc.language.iso eng
dc.publisher Nature Publishing Group
dc.rights © Nature Publishing Group. http://dx.doi.org/10.1038/nm.3127
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 syndrome
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/nm.3127
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.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/acceptedVersion

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