Innate frequency-discrimination hyperacuity in Williams-Beuren mice

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 interneu-rons 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.

Automated summary

Williams-Beuren syndrome (WBS) is a rare genetic disorder characterized by neurodevelopmental and cognitive deficits. However, individuals with WBS have enhanced musical and auditory abilities. Mouse models of WBS show improved frequency discrimination and frequency coding in the auditory cortex. This is caused by hyperexcitable interneurons in the auditory cortex and the downregulation of the neuropeptide receptor VIPR1, which is replicated by the haploinsufficiency of the WBS gene Gtf2ird1. VIPR1 is reduced in individuals with WBS and in cerebral organoids derived from human induced pluripotent stem cells with the WBS microdeletion. Manipulation of Vipr1 in interneurons mimics or reverses the cellular and behavioral phenotypes of WBS mice, suggesting that the Gtf2ird1-Vipr1 mechanism in auditory cortex interneurons may underlie the superior auditory acuity in WBS.