A Gap-Junction Mutation Reveals That Outer Hair Cell Extracellular Receptor Potentials Drive High-Frequency Cochlear Amplification

Snezana Levic, Victoria A Lukashkina, Patricio Simões, Andrei N Lukashkin, Ian J Russell

Research output: Contribution to journalArticlepeer-review

Abstract

Cochlear amplification enables the enormous dynamic range of hearing through amplifying cochlear responses to low- to moderate-level sounds and compressing them to loud sounds. Amplification is attributed to voltage-dependent electromotility of mechanosensory outer hair cells (OHCs) driven by changing voltages developed across their cell membranes. At low frequencies, these voltage changes are dominated by intracellular receptor potentials (RPs). However, OHC membranes have electrical low-pass filter properties that attenuate high-frequency RPs, which should potentially attenuate amplification of high-frequency cochlear responses and impede high-frequency hearing. We made intracellular and extracellular electrophysiological measurements from the organ of Corti of male and female mice of the CBA/J strain, with excellent high-frequency hearing, and from the CD-1 mouse strain, which has sensitive hearing below 12 kHz but loses high-frequency hearing within a few weeks postpartum. The CD-1 mouse strain was transfected with an A88V mutation of the connexin 30 gap-junction protein. By blocking the action of the GJ protein to reduce input resistance, the mutation increased the OHC extracellular RP (ERP) magnitude and rescued high-frequency hearing. However, by increasing the organ of Corti resistance, the mutation rescued high-frequency hearing through preserving the OHC extracellular RP (ERP) magnitude. We measured the voltage developed across the basolateral membranes of OHCs, which controls their electromotility, for low- to high-frequency sounds in male and female mice of the CD-1 strain that expressed the A88V mutation. We demonstrate that ERPs, not RPs, drive OHC motility and cochlear amplification at high frequencies because at high frequencies, ERPs are not frequency attenuated, exceed RPs in magnitude, and are appropriately timed to provide cochlear amplification. Cochlear amplification, which enables the enormous dynamic range of hearing, is attributed to voltage-dependent electromotility of the mechanosensory outer hair cells (OHCs) driven by sound-induced voltage changes across their membranes. OHC intracellular receptor potentials are electrically low-pass filtered, which should hinder high-frequency hearing. We measured the intracellular and extracellular voltages that control OHC electromotility in a mouse strain with impaired high-frequency hearing. A gap-junction mutation of the strain rescued high-frequency hearing, increased organ of Corti resistance, and preserved large OHC extracellular receptor potentials but reduced OHC intracellular receptor potentials and impaired low-frequency hearing. We concluded intracellular potentials drive OHC motility at low frequencies and extracellular receptor potentials drive OHC motility and cochlear amplification at high frequencies. [Abstract copyright: Copyright © 2022 the authors.]
Original languageEnglish
Pages (from-to)7875-7884
Number of pages9
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience
Volume42
Issue number42
DOIs
Publication statusPublished - 9 Sep 2022

Bibliographical note

Funding Information:
Received Nov. 11, 2021; revised Aug. 2, 2022; accepted Sep. 2, 2022. Author contributions: S.L., A.N.L., and I.J.R. designed research; S.L., V.A.L., P.S., A.N.L., and I.J.R. performed research; S.L., V.A.L., P.S., A.N.L., and I.J.R. analyzed data; and A.N.L. and I.J.R. wrote the paper. This work was funded by United Kingdom Medical Research Council Grant MR/W028956/1. P. Simões’s present address: School of Life Sciences, University of Sussex, Brighton BN19QG, United Kingdom. The authors declare no competing financial interests. Correspondence should be addressed to Andrei N. Lukashkin at a.lukashkin@brighton.ac.uk or Ian J. Russell at i.russell@brighton.ac.uk. https://doi.org/10.1523/JNEUROSCI.2241-21.2022 Copyright © 2022 the authors

Publisher Copyright:
Copyright © 2022 the authors.

Keywords

  • Animals
  • Mice, Inbred CBA
  • cochlea
  • gap junction
  • Male
  • Female
  • Hair Cells, Auditory, Outer - physiology
  • cochlear amplifier
  • Connexin 30 - genetics - metabolism
  • Gap Junctions
  • Connexin 30
  • receptor potential
  • Mice
  • outer hair cell
  • Mutation - genetics
  • Cochlea - physiology

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