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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. Ministerio de Ciencia, Innovacion y Universidades FPU13/01867 Alba Navarro-Romero Ministerio de Ciencia e Innovacion BES-2016-077950 Lorena Galera-Lopez Ministerio de Ciencia e Innovacion RTI2018-099282-B-I00 Andres Ozaita Ministerio de Ciencia e Innovacion SAF2017-84060-R Rafael Maldonado Generalitat de Catalunya 2017SGR-669 Rafael Maldonado Ministerio de Ciencia e Innovacion SAF2016-78508-R Victoria Campuzano Basque Country Government IT1454-22 Rafael Rodriguez-Puertas Instituto de Salud Carlos III PI20/00153, co-funded by the European Union (ERDF "A way to make Europe") Rafael Rodriguez-Puertas Institucio Catalana de Recerca i Estudis Avancats Rafael Maldonado Ministerio de Economia y Competitividad #MDM-2014-0370 Alba Navarro-Romero Ministerio de Economia y Competitividad #MDM-2014-0370 Eduardo Eyras Ministerio de Ciencia e Innovacion PRE2019-087644 Lucia de los Reyes-Ramirez Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Andres Ozaita Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Rafael Maldonado Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Victoria Campuzano Ministerio de Economia y Competitividad FEDER Alba Navarro-Romero Ministerio de Economia y Competitividad FEDER Eduardo Eyras Ministerio de Economia y Competitividad IPEP MdM-2017 Eduardo Eyras Ministerio de Ciencia e Innovacion UE Andres Ozaita Ministerio de Ciencia e Innovacion UE Rafael Maldonado Ministerio de Economia y Competitividad UE Alba Navarro-Romero Ministerio de Ciencia e Innovacion UE Victoria Campuzano Ministerio de Economia y Competitividad EU Eduardo Eyras FRAXA Research Foundation Lorena Galera-Lopez The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.

Williams-Beuren syndrome (WBS) is a rare developmental disorder caused by the deletion of a 1.5 Mb region in chromosome 7 (7q11.23). WBS has been recently modelled by a mutant mouse line having a complete deletion (CD) of the equivalent locus on mouse chromosome 5, thus resembling the genetic defect found in WBS patients. CD mice have been shown to have physical and neurobehavioral abnormalities that recapitulate most of the symptoms associated with human WBS, including cardiovascular, motor, social, emotional and sensory alterations. This model has been largely used to investigate the etiopathological mechanisms of WBS; nonetheless, pharmacological therapies for this syndrome have not been identified yet. Here we propose a novel treatment for WBS, chlorzoxazone (CHLOR), i.e., a molecule targeting calcium-activated large conductance potassium (BKCa) channels, since a reduction in the expression of these channels has been recently described in neurons from WBS patients, as well as in other rare developmental pathologies. Our results demonstrate both the acute and chronic effects of CHLOR on some major pathological phenotypes of CD mice, including several behavioural alterations and cardiac hypertrophy. We conclude that BKCa channels are a therapeutic target of high potential for clinical applications and are likely to play a key role in the etiopathology of WBS.

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.

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there are currently no effective treatments. We investigated the progression of behavioral deficits present in WBS complete deletion (CD) mice, after chronic treatment with curcumin, verapamil, and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and, thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism. CD mice showed an increased density of activated microglia in the motor cortex and CA1 hippocampal region, which was prevented by co-treatment. Behavioral improvement correlated with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation to the control of synaptic transmission, and inflammation. Therefore, the results show that co-treatment prevented behavioral deficits by recovering altered gene expression in the cortex of CD mice and reducing activated microglia. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients. This work was supported by Ministerio de Ciencia e Innovación (SAF 2017-83039-R to GE and SAF 2016-78508-R (AEI/MINEICO/FEDER, UE) to VC) from the association “Autour des Williams” to VC and Generalitat de Catalunya (2017-SGR1794) to VC.

Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there currently are not any effective treatments. We investigated the progression of behavioral deficits present in CD (complete deletion) mice, a rodent model of WBS, after chronic treatment with curcumin, verapamil and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism in CD mice. Behavioral improvement correlates with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation with the control of synaptic transmission. Moreover, CD mice showed an increased activated microglia density in different brain regions, which was prevented by treatment. Therefore, results show that treatment prevented behavioral deficits by recovering altered gene expression in cortex of CD mice, reducing activated microglia and normalizing Bdnf expression levels. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice, and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

Williams-Beuren syndrome (WBS) is a rare disorder caused by a heterozygous deletion of 26-28 contiguous genes that affects the brain and cardiovascular system. Here, we investigated whether WBS affects aortic structure and function in the complete deletion (CD) mouse model harbouring the most common deletion found in WBS patients. Thoracic aortas from 3-4 months-old male CD mice and wild-type littermates were mounted in wire myographs or were processed for histomorphometrical analysis. Nitric oxide synthase (NOS) isoforms and oxidative stress levels were assessed. Ascending aortas from young adult CD mice showed moderate (50%) luminal stenosis, whereas endothelial function and oxidative stress were comparable to wild-type. CD mice showed greater contractions to KCl. However, α1-adrenergic contractions to phenylephrine, but not with a thromboxane analogue, were compromised. Decreased phenylephrine responses were not affected by selective inducible NOS blockade with 1400 W, but were prevented by the non-selective NOS inhibitor L-NAME and the selective neuronal NOS inhibitor SMTC. Consistently, CD mice showed increased neuronal NOS expression in aortas. Overall, aortic stenosis in CD mice coexists with excessive nNOS-derived NO signaling that compromises ascending aorta α1-adrenergic contractions. We suggest that increased neuronal NOS signaling may act as a physiological 'brake' against the detrimental effects of stenosis. This work was supported by Ministerio de Ciencia e Innovación [[SAF2014-56111-R to FJA] and [SAF2016-78508-R (AEI/MINEICO/FEDER, UE) to VC]]; and Generalitat de Catalunya [2017-SGR-645 to FJA].

Data de publicació electrònica: 30-08-2019 Williams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by moderate intellectual disability and learning difficulties alongside behavioral abnormalities such as hypersociability. Several structural and functional brain alterations are characteristic of this syndrome, as well as disturbed sleep and sleeping patterns. However, the detailed physiological mechanisms underlying WBS are mostly unknown. Here, we characterized the cortical dynamics in a mouse model of WBS previously reported to replicate most of the behavioral alterations described in humans. We recorded the laminar local field potential generated in the frontal cortex during deep anesthesia and characterized the properties of the emergent slow oscillation activity. Moreover, we performed micro-electrocorticogram recordings using multielectrode arrays covering the cortical surface of one hemisphere. We found significant differences between the cortical emergent activity and functional connectivity between wild-type mice and WBS model mice. Slow oscillations displayed Up states with diminished firing rate and lower high-frequency content in the gamma range. Lower firing rates were also recorded in the awake WBS animals while performing a marble burying task and could be associated with the decreased spine density and thus synaptic connectivity in this cortical area. We also found an overall increase in functional connectivity between brain areas, reflected in lower clustering and abnormally high integration, especially in the gamma range. These results expand previous findings in humans, suggesting that the cognitive deficits characterizing WBS might be associated with reduced excitability, plus an imbalance in the capacity to functionally integrate and segregate information. This work was supported by EU H2020 Research and Innovation Programme under Grant Agreement No. 720270 (HBP SGA2), BFU2017-85048-R Spanish Ministry of Science and CERCA Programme/Generalitat de Catalunya to MVSV.

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a heterozygous deletion of 26-28 genes at chromosome band 7q11.23. The complete deletion (CD) mouse model mimics the most common deletion found in WBS patients and recapitulates most neurologic features of the disorder along with some cardiovascular manifestations leading to significant cardiac hypertrophy with increased cardiomyocytes' size. Epigallocatechin-3-gallate (EGCG), the most abundant catechin found in green tea, has been associated with potential health benefits, both on cognition and cardiovascular phenotypes, through several mechanisms. We aimed to investigate the effects of green tea extracts on WBS-related phenotypes through a phase I clinical trial in mice. After feeding CD animals with green tea extracts dissolved in the drinking water, starting at three different time periods (prenatal, youth and adulthood), a set of behavioral tests and several anatomical, histological and molecular analyses were performed. Treatment resulted to be effective in the reduction of cardiac hypertrophy and was also able to ameliorate short-term memory deficits of CD mice. Taken together, these results suggest that EGCG might have a therapeutic and/or preventive role in the management of WBS. This work was supported by the Spanish Ministry of Economy and Competitiveness (grant SAF2012-40036, and SAF2016-78508-R(AEI/MINEICO/FEDER, UE) to VC; “Programa de Excelencia Maria de Maeztu” MDM-2014-0370, the Generalitat de Catalunya (2014SGR1468 and ICREA Acadèmia) to LAPJ; AGAUR FI-DGR/2013 fellowship to CB.