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Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice
Cell ( IF 64.5 ) Pub Date : 2022-09-23 , DOI: 10.1016/j.cell.2022.08.022
Christopher M Davenport 1 , Brett J W Teubner 1 , Seung Baek Han 1 , Mary H Patton 1 , Tae-Yeon Eom 1 , Dusan Garic 1 , Benjamin J Lansdell 1 , Abbas Shirinifard 1 , Ti-Cheng Chang 2 , Jonathon Klein 3 , Shondra M Pruett-Miller 3 , Jay A Blundon 1 , Stanislav S Zakharenko 1
Affiliation  

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.



中文翻译:

威廉姆斯-博伊伦综合征小鼠的先天频率辨别超敏锐度

Williams-Beuren 综合征 (WBS) 是一种罕见疾病,由约 27 个连续基因的半合子微缺失引起。尽管存在神经发育和认知缺陷,WBS 患者仍保留或增强了音乐和听觉能力,这可能有助于深入了解听觉感知的遗传基础。在这里,我们报告 WBS 小鼠模型天生增强了频率辨别敏锐度,并改善了听觉皮层 (ACx) 的频率编码。化学遗传学救援表明频率辨别超敏是由 ACx 中过度兴奋的中间神经元引起的。一种 WBS 基因Gtf2ird1的单倍体不足通过下调神经肽受体 VIPR1 来复制 WBS 表型。VIPR1 在患有 WBS 的个体的 ACx 中以及在源自具有 WBS 微缺失的人类诱导多能干细胞的大脑类器官中减少。ACx 中间神经元中Vipr1 的缺失或过度表达分别模拟或逆转了 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 中较高听觉敏锐度的基础。

更新日期:2022-09-23
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