Navarro Romero, Alba, 1990-Galera López, Lorena, 1993-Ortiz Romero, Paula, 1994-Llorente-Ovejero, AlbertoLos Reyes-Ramírez, Lucía deBengoetxea de Tena, IkerGarcia-Elias Heras, AnnaMas Stachurska, AleksandraReixachs i Solé, MarinaPastor, AntonioTorre Fornell, Rafael de laMaldonado, Rafael, 1961-Benito Villabriga, BegoñaEyras Jiménez, EduardoRodríguez-Puertas, RafaelCampuzano Uceda, María VictoriaOzaita Mintegui, Andrés, 1969-2022-11-162022-11-162022Navarro-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.725602050-084Xhttp://hdl.handle.net/10230/54885Williams-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.application/pdfeng© 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.info:eu-repo/semantics/articlehttp://dx.doi.org/10.7554/eLife.72560Williams–Beuren syndromeCannabinoid type-1 receptorEndocannabinoid systemIntellectual disabilityMedicineMouseinfo:eu-repo/semantics/openAccess