Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome
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 amelio...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/72560 |
| _version_ | 1797995643102298112 |
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| author | Alba Navarro-Romero Lorena Galera-López Paula Ortiz-Romero Alberto Llorente-Ovejero Lucía de los Reyes-Ramírez Iker Bengoetxea de Tena Anna Garcia-Elias Aleksandra Mas-Stachurska Marina Reixachs-Solé Antoni Pastor Rafael de la Torre Rafael Maldonado Begoña Benito Eduardo Eyras Rafael Rodríguez-Puertas Victoria Campuzano Andres Ozaita |
| author_facet | Alba Navarro-Romero Lorena Galera-López Paula Ortiz-Romero Alberto Llorente-Ovejero Lucía de los Reyes-Ramírez Iker Bengoetxea de Tena Anna Garcia-Elias Aleksandra Mas-Stachurska Marina Reixachs-Solé Antoni Pastor Rafael de la Torre Rafael Maldonado Begoña Benito Eduardo Eyras Rafael Rodríguez-Puertas Victoria Campuzano Andres Ozaita |
| author_sort | Alba Navarro-Romero |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:04:53Z |
| format | Article |
| id | doaj.art-30bd7532970b48ce8dab47e31977a19e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:04:53Z |
| publishDate | 2022-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-30bd7532970b48ce8dab47e31977a19e2022-12-22T04:30:16ZengeLife Sciences Publications LtdeLife2050-084X2022-10-011110.7554/eLife.72560Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndromeAlba Navarro-Romero0Lorena Galera-López1Paula Ortiz-Romero2Alberto Llorente-Ovejero3Lucía de los Reyes-Ramírez4Iker Bengoetxea de Tena5Anna Garcia-Elias6Aleksandra Mas-Stachurska7https://orcid.org/0000-0003-4947-4111Marina Reixachs-Solé8Antoni Pastor9Rafael de la Torre10Rafael Maldonado11https://orcid.org/0000-0002-4359-8773Begoña Benito12Eduardo Eyras13Rafael Rodríguez-Puertas14Victoria Campuzano15Andres Ozaita16https://orcid.org/0000-0002-2239-7403Laboratory of Neuropharmacology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, SpainLaboratory of Neuropharmacology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, SpainDepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, and centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, SpainDepartment of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country, Leioa, SpainLaboratory of Neuropharmacology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, SpainDepartment of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country, Leioa, SpainLaboratory of Neuropharmacology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, SpainHospital del Mar Medical Research Institute (IMIM), Autonomous University of Barcelona, Barcelona, SpainEMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia; The John Curtin School of Medical Research, Australian National University, Canberra, AustraliaHospital del Mar Medical Research Institute (IMIM), Barcelona, SpainHospital del Mar Medical Research Institute (IMIM), Barcelona, SpainLaboratory of Neuropharmacology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, SpainGroup of Cardiovascular Experimental and Translational Research (GET-CV), Vascular Biology and Metabolism, Vall d’Hebron Research Institute (VHIR),, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBER-CV), Instituto de Salud Carlos III, Madrid, SpainEMBL Australia Partner Laboratory Network at the Australian National University, Canberra, Australia; The John Curtin School of Medical Research, Australian National University, Canberra, Australia; Hospital del Mar Medical Research Institute (IMIM), Barcelona, SpainDepartment of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country, Leioa, Spain; Neurodegenerative Diseases, Biocruces Bizkaia Health Research Institute, Barakaldo, SpainDepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of Barcelona, and centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, SpainLaboratory of Neuropharmacology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, SpainWilliams–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.https://elifesciences.org/articles/72560Williams–Beuren syndromeintellectual disabilityendocannabinoid systemcannabinoid type-1 receptor |
| spellingShingle | Alba Navarro-Romero Lorena Galera-López Paula Ortiz-Romero Alberto Llorente-Ovejero Lucía de los Reyes-Ramírez Iker Bengoetxea de Tena Anna Garcia-Elias Aleksandra Mas-Stachurska Marina Reixachs-Solé Antoni Pastor Rafael de la Torre Rafael Maldonado Begoña Benito Eduardo Eyras Rafael Rodríguez-Puertas Victoria Campuzano Andres Ozaita Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome eLife Williams–Beuren syndrome intellectual disability endocannabinoid system cannabinoid type-1 receptor |
| title | Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome |
| title_full | Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome |
| title_fullStr | Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome |
| title_full_unstemmed | Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome |
| title_short | Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome |
| title_sort | cannabinoid signaling modulation through jzl184 restores key phenotypes of a mouse model for williams beuren syndrome |
| topic | Williams–Beuren syndrome intellectual disability endocannabinoid system cannabinoid type-1 receptor |
| url | https://elifesciences.org/articles/72560 |
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