PT  - JOURNAL ARTICLE
AU  - Alba Navarro-Romero
AU  - Lorena Galera-López
AU  - Paula Ortiz-Romero
AU  - Alberto Llorente-Ovejero
AU  - Lucía de los Reyes-Ramírez
AU  - Aleksandra Mas-Stachurska
AU  - Marina Reixachs-Solé
AU  - Antoni Pastor
AU  - Rafael de la Torre
AU  - Rafael Maldonado
AU  - Begoña Benito
AU  - Eduardo Eyras
AU  - Rafael Rodríguez-Puertas
AU  - Victoria Campuzano
AU  - Andrés Ozaita
TI  - Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams-Beuren syndrome
AID  - 10.1101/2021.08.16.456474
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.16.456474
4099  - http://biorxiv.org/content/early/2021/08/19/2021.08.16.456474.short
4100  - http://biorxiv.org/content/early/2021/08/19/2021.08.16.456474.full
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 available treatments to 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 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 sub-chronic (10 d) JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiac 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.Competing Interest StatementThe authors have declared no competing interest.