Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome
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- dc.contributor.author Navarro Romero, Alba, 1990-
- dc.contributor.author Galera López, Lorena, 1993-
- dc.contributor.author Ortiz Romero, Paula, 1994-
- dc.contributor.author Llorente-Ovejero, Alberto
- dc.contributor.author Los Reyes-Ramírez, Lucía de
- dc.contributor.author Bengoetxea de Tena, Iker
- dc.contributor.author Garcia-Elias Heras, Anna
- dc.contributor.author Mas Stachurska, Aleksandra
- dc.contributor.author Reixachs i Solé, Marina
- dc.contributor.author Pastor, Antonio
- dc.contributor.author Torre Fornell, Rafael de la
- dc.contributor.author Maldonado, Rafael, 1961-
- dc.contributor.author Benito Villabriga, Begoña
- dc.contributor.author Eyras Jiménez, Eduardo
- dc.contributor.author Rodríguez-Puertas, Rafael
- dc.contributor.author Campuzano Uceda, María Victoria
- dc.contributor.author Ozaita Mintegui, Andrés, 1969-
- dc.date.accessioned 2022-11-16T07:37:58Z
- dc.date.available 2022-11-16T07:37:58Z
- dc.date.issued 2022
- dc.description.abstract Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.
- dc.description.sponsorship This study was supported by Ministerio de Economía, Innovación y Competitividad (MINECO), Spain #RTI2018-099282-B-I00B to A.O., #SAF2017-84060-R to R.M.; Generalitat de Catalunya, Spain (2017SGR-669 to R.M.); Ministerio de Ciencia e Innovación (SAF2016-78508-R; AEI/MINEICO/FEDER, UE) to VC. Basque Government IT1454-22 to the 'Neurochemistry and Neurodegeneration' consolidated research group to R R-P. Instituto de Salud Carlos III (PI20/00153, co-funded by the European Union [ERDF 'A way to make Europe']) to R R-P. ICREA (Institució Catalana de Recerca i Estudis Avançats, Spain) Academia to A.O. and R.M. Grant 'Unidad de Excelencia María de Maeztu', funded by the MINECO (#MDM-2014-0370); IPEP MdM 2017 to A.O. and E.E. FEDER, European Commission funding is also acknowledged.
- dc.format.mimetype application/pdf
- dc.identifier.citation Navarro-Romero A, Galera-López L, Ortiz-Romero P, Llorente-Ovejero A, de Los Reyes-Ramírez L, Bengoetxea de Tena I, Garcia-Elias A, Mas-Stachurska A, Reixachs-Solé M, Pastor A, de la Torre R, Maldonado R, Benito B, Eyras E, Rodríguez-Puertas R, Campuzano V, Ozaita A. Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome. Elife. 2022 Oct 11;11:e72560. DOI: 10.7554/eLife.72560
- dc.identifier.doi http://dx.doi.org/10.7554/eLife.72560
- dc.identifier.issn 2050-084X
- dc.identifier.uri http://hdl.handle.net/10230/54885
- dc.language.iso eng
- dc.publisher eLife
- dc.relation.ispartof Elife. 2022 Oct 11;11:e72560
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-099282-B-I00
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-84060-R
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2016-78508-R
- dc.rights © 2022, Navarro-Romero, Galera-López et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword Williams–Beuren syndrome
- dc.subject.keyword Cannabinoid type-1 receptor
- dc.subject.keyword Endocannabinoid system
- dc.subject.keyword Intellectual disability
- dc.subject.keyword Medicine
- dc.subject.keyword Mouse
- dc.title Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion