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 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 Statement
The authors have declared no competing interest.
Footnotes
Funding A.N-R was the recipient of a predoctoral fellowship (Ministerio de Educación y Cultura, Spain), L.G-L. was supported by predoctoral fellowship by FPI (MINE- ICO/FEDER, EU). 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 IT975-16 to the “Neurochemistry and Neurodegeneration” consolidated research group 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.