Williams-Beuren综合征(WBS)是由染色体微缺失(7q11.23)引起的神经发育障碍。WBS已经通过具有等效小鼠基因座的完全缺失(CD)的小鼠品系建模。该模型已被广泛用于研究WBS的病因病理机制,虽然药物疗法尚未确定。令人惊讶的是,到目前为止,CD小鼠主要在成年期进行测试,尽管WBS的发展性质和潜在治疗的早期时机至关重要。在这里,我们首次提供了婴儿期和青春期两性CD小鼠的表型特征,即,从出生到7周龄。两性的CD幼崽显示身体生长减少,感觉发育延迟,以及超声发声和探索行为的模式改变。青少年CD小鼠表现出运动和听觉惊吓反应降低,改变了社会互动和交流,后者在雌性小鼠中更为明显。两种性别的青少年CD突变体也显示出大脑重量减少,皮质和海马树突长度,和脊柱密度。我们的发现强调了早期神经行为改变作为WBS病理学生物标志物的关键相关性,青春期对于确定这种神经系统疾病的新治疗靶标的重要性。
Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a chromosomic microdeletion (7q11.23). WBS has been modeled by a mouse line having a complete deletion (CD) of the equivalent mouse locus. This model has been largely used to investigate the etiopathological mechanisms of WBS, although pharmacological therapies have not been identified yet. Surprisingly, CD mice were so far mainly tested in adulthood, despite the developmental nature of WBS and the critical relevance of early timing for potential treatments. Here we provide for the first time a phenotypic characterization of CD mice of both sexes during infancy and adolescence, i.e., between birth and 7 weeks of age. CD pups of both sexes showed reduced body growth, delayed sensory development, and altered patterns of ultrasonic vocalizations and exploratory behaviors. Adolescent CD mice showed reduced locomotion and acoustic startle response, and altered social interaction and communication, the latter being more pronounced in female mice. Juvenile CD mutants of both sexes also displayed reduced brain weight, cortical and hippocampal dendritic length, and spine density. Our findings highlight the critical relevance of early neurobehavioral alterations as biomarkers of WBS pathology, underlying the importance of adolescence for identifying novel therapeutic targets for this neurological disorder.