TY - JOUR TI - Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome AU - Navarro-Romero, Alba AU - Galera-López, Lorena AU - Ortiz-Romero, Paula AU - Llorente-Ovejero, Alberto AU - de los Reyes-Ramírez, Lucía AU - Bengoetxea de Tena, Iker AU - Garcia-Elias, Anna AU - Mas-Stachurska, Aleksandra AU - Reixachs-Solé, Marina AU - Pastor, Antoni AU - de la Torre, Rafael AU - Maldonado, Rafael AU - Benito, Begoña AU - Eyras, Eduardo AU - Rodríguez-Puertas, Rafael AU - Campuzano, Victoria AU - Ozaita, Andres A2 - Emoto, Noriaki A2 - Barton, Matthias A2 - Kwang Mook, Jung VL - 11 PY - 2022 DA - 2022/10/11 SP - e72560 C1 - eLife 2022;11:e72560 DO - 10.7554/eLife.72560 UR - https://doi.org/10.7554/eLife.72560 AB - 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. KW - Williams–Beuren syndrome KW - intellectual disability KW - endocannabinoid system KW - cannabinoid type-1 receptor JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -