Vascular abnormalities in heart and brain are associated with cardiovascular and neurological symptoms in a novel mouse model for Williams syndrome

Abstract

Williams syndrome is a developmental disorder caused by a microdeletion entailing loss of a single copy of 25-27 genes on chromosome 7q11.23. Patients with Williams syndrome suffer from cardiovascular and neuropsychological symptoms. So far, the structural abnormalities of the cardiovascular system in Williams syndrome have been attributed to the loss of a copy of the elastin (ELN) gene. In contrast, the neuropsychological consequences of Williams syndrome, including motor deficits, hypersociability and cognitive impairments, have been mainly attributed to altered expression of transcription factors like LIMK1, GTF2I and GTF2IRD1, while the potential secondary impact of altered cerebrovascular function has been largely ignored. To study the relation between the mutation underlying Williams syndrome and vascularization of not only the heart but also that of the brain, we generated a mouse model with a relatively long microdeletion, including theNcf1gene to reduce the confounding impact of hypertension. The affected mice had an elongated and tortuous aorta, but unlike inElnhaploinsufficient mice, there were no signs of structural cardiac hypertrophy. Our Williams syndrome mice had similar structural abnormalities in their coronary and brain vessels, showing disorganized extracellular matrices of the vessel walls. Moreover, our mouse model faithfully replicated both cardiovascular and neurological symptoms of Williams syndrome, highlighting that accurate non-invasive evaluation of complex vascular abnormalities is feasible. Altogether, we present evidence for vascular malformations that are similar in heart and brain, suggesting that cardiovascular and neurological symptoms can both by impacted by changes in the vascular structure in patients with Williams syndrome.

The modified elevated gap interaction test: A novel paradigm to assess social preference

“…A potential confounder for the interpretation of social behavior is the presence of repetitive or hyperactive behavior that could increase the overall number of crossings. Before evaluating social phenotypes of mutant mice, we, therefore, first focused on repetitive and hyperactive behavior in a mouse model for ASD with a known hyperactive phenotype, global Shank2 knockout mice 18 , and a novel mouse model for WBS 32 , in comparison to their respective wild-type littermates. When comparing data on all crossings (gap and sides, both videos), Shank2 -/- mice showed a remarkable three-fold increase in number of crossings ( p <0.001), a marked decrease in duration of crossings ( p <0.001), and a milder increase in time spent on crossings ( p <0.05; Fig 4A).…”

“…In MEGIT, this is quantified as an increase in the durations of social interaction and social approach. To test whether MEGIT is sensitive enough to reliably detect phenotypes in social behavior, two genetic mouse models with known alterations in their social behavior 18,20,28,32 were subsequently tested. In line with the behavior typically observed in humans carrying these mutations, we found hypersocial behavior in WBS mice, whereas Shank2 -/- mice showed a markedly decreased social preference.…”

“…Data were obtained from adult (8-20 weeks) mice that were confronted with juvenile (22-31 days) mice of either sex. All mice had a C57BL/6J background (Charles River), while in specific experiments germline Shank2 -/-18,20 , or WBS 32 mice were used. Mutant lines were bred in-house and compared to their wild-type littermates.…”

“…Mutant lines were bred in-house and compared to their wild-type littermates. To generate the WBS mouse model, CRISPR/Cas9 technology was used to remove the genes between Ncf1 and Fkbp6 on mouse chromosome 5, corresponding to the same genes on chromosome 7q11.23 in humans 32,33 . All mice were group housed in enriched cages, had ad libitum access to food and water and were held on a 12:12h light/dark cycle.…”