Cortical Mechanisms of Innate Frequency Discrimination

St. Jude Children'S Research Hospital, Memphis TN

Investigators

Abstract

Abstract Throughout evolution, the ability to distinguish acoustic frequencies from each other and from the surrounding auditory environment has been essential for survival. In humans, this ability remains fundamental to everyday hearing, linguistics, and musicality, yet the neural and molecular mechanisms underlying frequency discrimination are not well understood. GABAergic interneurons (INs) in the auditory cortex (ACx) have been implicated as the cellular loci underlying behaviors that rely on frequency-discrimination abilities. This notion has been confirmed by the recent discovery that hyperexcitability of GABAergic INs in the ACx causes frequency- discrimination hyperacuity in models of Williams-Beuren syndrome (WBS), a neurodevelopmental disorder associated with cognitive and learning impairments that spares or enhances auditory functions. We recently showed that mouse models of WBS have innately superior frequency-discrimination acuity that results from hyperexcitable GABAergic INs in the ACx. Among the WBS genes, Gtf2ird1 is the only one whose haploinsufficiency replicates WBS phenotypes by downregulating vasoactive intestinal polypeptide receptor 1 (VIPR1). VIPR1 deficiency causes hyperexcitability of GABAergic INs in the ACx and improves frequency- discrimination abilities. Preliminary data indicated that VIPR1 acts through voltage-gated calcium channels (VGCCs), but the identity of specific VGCCs is unknown. VIPR1 overexpression in those cells reverses the cellular and behavioral phenotypes of WBS mice. This finding indicates that the VIPR1-dependent mechanism in cortical INs underlies the mechanism of superior frequency-discrimination acuity in WBS mice. Furthermore, this mechanism improves frequency-coding capabilities in the ACx, as evidenced by 2-photon imaging of neuronal ensemble activities in awake mice. We surmised that we could employ the reverse-translational approach by using these findings in a disease model to gain insights into the normal physiology of frequency discrimination by focusing on VIPR1 signaling in cortical INs. Therefore, we propose the following hypothesis: VIPR1 signaling in a certain subtype of GABAergic INs (PV+, SOM+, or VIP+) in the ACx underlies frequency- discrimination abilities and frequency coding through bidirectional tuning of IN excitability via VGCCs. To test this hypothesis, we propose 3 Specific Aims: In Aim 1, we will identify the subtype of cortical GABAergic INs in which VIPR1 signaling regulates frequency discrimination. In Aim 2, we will elucidate the mechanistic link between VIPR1 signaling and IN hyperexcitability in the ACx by identifying the VGCC involved. In Aim 3, we will determine how VIPR1 signaling affects frequency coding in the ACx. The results of these experiments will substantially advance our knowledge about the cortical mechanism of frequency discrimination.