Williams-Beuren Syndrome (WBS) is a rare disorder that causes neurocognitive and developmental deficits. However, musical and auditory abilities are retained or even improved in WBS patients. Scientists at St. Jude Children’s Research Hospital have identified the mechanism responsible for this ability in disease models. The results were published today in cell.
Understanding the causes of superior hearing in WBS patients may provide a target for treatment of the disease and help advance research into the ability to discriminate between sounds. WBS provides insight into the mechanisms underlying improved hearing abilities. For example, some people with WBS have pitch perfect, which is the ability to distinguish between notes or frequencies without a reference manual.
“WBS stands out among neurodevelopmental disorders because, despite severe learning disabilities, children with this disorder may have a higher prevalence of superior musical and language skills than children in the general population,” said corresponding author Stanislav Zakharenko, MD, Ph.D., St .Jude Department of Developmental Neurobiology. “We were intrigued by this and wanted to learn more about how a disorder caused by the loss of 27 genes can help people gain superior auditory processing ability.”
Excited neurons in the auditory cortex
WBS mouse models have an improved ability to discriminate between sound frequencies. These mice also have improved frequency encoding in the auditory cortex, the part of the brain that processes sound. The researchers showed that the enhanced ability to discriminate between frequencies is caused by overexcitable interneurons in the auditory cortex.
To understand the cell biology underlying the improved hearing abilities in WBS patients, the researchers performed an RNAseq experiment. The data led the researchers to a neuropeptide receptor called VIPR1, which is reduced in the auditory cortex of people with WBS. Reduction of VIPR1 was also found in cerebral organoids, advanced models made in the laboratory using human induced pluripotent stem cells.
The scientists found that the transcription factor Gtf2ird1, which is encoded by one of the 27 genes that are lost in patients with WBS, regulates VIPR1. Deleting or overexpressing VIPR1 in the auditory cortex can mimic or reverse the auditory effects seen in WBS. That’s the way it is Gtf2ird1 Downregulation of VIPR1 responsible for the effects of WBS on hearing.
“I didn’t know much about VIPR1 before it appeared in our data because the role of this family of receptors in the brain is underestimated compared to other neuromodulators or neurotransmitter receptors,” said lead author Christopher Davenport, St. Jude’s Department of Developmental Neurobiology. “Our results show that they can strongly influence information processing and behavior and are probably also relevant for other behaviors and diseases.”
“This work suggests that reducing neuronal hyperexcitability may be a general mechanism to treat WBS by targeting VIPR1,” Zakharenko said. “It also opens up new directions for learning about musicality and how our brain distinguishes sounds based on these insights in WBS models.”
Materials provided by St. Jude Children’s Research Hospital. Note: Content can be edited for style and length.