Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.
Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice.
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DOI：
10.1016/j.cell.2022.08.022
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发表时间：
2022-10-13
期刊：
影响因子：
64.5
通讯作者：
Zakharenko, Stanislav S.
中科院分区：
文献类型：
--
作者：
Davenport, Christopher M.;Teubner, Brett J. W.;Han, Seung Baek;Patton, Mary H.;Eom, Tae-Yeon;Garic, Dusan;Lansdell, Benjamin J.;Shirinifard, Abbas;Chang, Ti-Cheng;Klein, Jonathon;Pruett-Miller, Shondra M.;Blundon, Jay A.;Zakharenko, Stanislav S.
Williams-Beuren综合征(WBS)是一种罕见的疾病，由~27个连续基因的半合子微缺失引起。尽管有神经发育和认知缺陷，但WBS患者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，我们报告了WBS的小鼠模型具有天生增强的频率辨别敏锐度和改善的听觉皮质(ACX)的频率编码。化学救治表明，频率辨别性超敏是由ACX内过度兴奋的中间神经元引起的。WBS基因Gtf2ird1的单倍性不足通过下调神经肽受体VIPR1来复制WBS表型。WBS患者ACX和WBS微缺失的人诱导的多能干细胞衍生的脑器官中VIPR1减少。Vipr1在ACX中间神经元中的缺失或过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具有较高听觉敏感度的基础。威廉姆斯-博伦综合征是一种神经发育障碍，也与备用或优越的听觉能力有关。这种情况是由Gtf2ird1单倍体不足导致的神经肽受体VIPR1下调引起的。
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 insight into the genetic basis of auditory perception. Here we report that 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 ACx. Haploinsufficiency of one WBS gene, Gtf2ird1, replicated WBS phenotypes by downregulating the neuropeptide receptor VIPR1. VIPR1 is reduced in ACx of individuals with WBS and in 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. Williams-Beuren syndrome is a neurodevelopmental disorder that is also associated with spared or superior auditory abilities. This condition is caused by a down- regulation of the neuropeptide receptor VIPR1, driven by Gtf2ird1 haploinsufficiency.
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