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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 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].

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.