PDF(Pubmed)
Abstract：
Williams-Beuren syndrome (WBS) is a rare disorder caused by hemizygous microdeletion of ∼27 contiguous genes. Despite neurodevelopmental and cognitive deficits, individuals with WBS have spared or enhanced musical and auditory abilities, potentially offering an insight into the genetic basis of auditory perception. Here, we report that the mouse models of WBS have innately enhanced frequency-discrimination acuity and improved frequency coding in the auditory cortex (ACx). Chemogenetic rescue showed frequency-discrimination hyperacuity is caused by hyperexcitable interneurons in the ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in the ACx of individuals with WBS and in the cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Vipr1 deletion or overexpression in ACx interneurons mimicked or reversed, respectively, the cellular and behavioral phenotypes of WBS mice. Thus, the Gtf2ird1-Vipr1 mechanism in ACx interneurons may underlie the superior auditory acuity in WBS.
摘要：
Williams-Beuren综合征（WBS）是由~27个连续基因的半合子微缺失引起的一种罕见疾病。尽管存在神经发育和认知缺陷，患有WBS的人幸免或增强了音乐和听觉能力，可能提供对听觉感知的遗传基础的洞察。这里,我们报道,WBS小鼠模型在听觉皮层(ACx)具有天生增强的频率辨别敏锐度和改善的频率编码.化学遗传学挽救显示，频率辨别过强是由ACx中过度兴奋的中间神经元引起的。一个WBS基因的单倍体不足，Gtf2ird1，通过下调神经肽受体VIPR1复制WBS表型。VIPR1在患有WBS的个体的ACx中和在源自具有WBS微缺失的人诱导多能干细胞的脑类器官中降低。在ACx中间神经元中，Vipr1缺失或过表达被模仿或逆转，分别,WBS小鼠的细胞和行为表型。因此，ACx中间神经元中的Gtf2ird1-Vipr1机制可能是WBS中上听觉敏锐度的基础。
