Etiology of distinct membrane excitability in pre- And posthearing auditory neurons relies on activity of cl- channel TMEM16A

Xiao Dong Zhang, Jeong Han Lee, Ping Lv, Wei Chun Chen, Hyo Jeong Kim, Dongguang Wei, Wenying Wang, Choong Ryoul Sihn, Karen Jo Doyle, Jason R. Rock, Nipavan Chiamvimonvat, Ebenezer N. Yamoah

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The developmental rehearsal for the debut of hearing is marked by massive changes in the membrane properties of hair cells (HCs) and spiral ganglion neurons (SGNs). Whereas the underlying mechanisms for the developing HC transition to mature stage are understood in detail, the maturation of SGNs from hyperexcitable prehearing to quiescent posthearing neurons with broad dynamic range is unknown. Here, we demonstrated using pharmacological approaches, caged-Ca2+ photolysis, and gramicidin patch recordings that the prehearing SGN uses Ca2+-activated Cl- conductance to depolarize the resting membrane potential and to prime the neurons in a hyperexcitable state. Immunostaining of the cochlea preparation revealed the identity and expression of the Ca2+-activated Cl- channel transmembrane member 16A (TMEM16A) in SGNs. Moreover, null deletion of TMEM16A reduced the Ca2+-activated Cl- currents and action potential firing in SGNs. To determine whether Cl- ions and TMEM16A are involved in the transition between pre- and posthearing features of SGNs we measured the intracellular Cl- concentration [Cl-]i in SGNs. Surprisingly, [Cl-]i in SGNs from prehearing mice was ∼90 mM, which was significantly higher than posthearing neurons, ∼20 mM, demonstrating discernible altered roles of Cl- channels in the developing neuron. The switch in [Cl-]i stems from delayed expression of the development of intracellular Cl- regulating mechanisms. Because the Cl- channel is the only active ionselective conductance with a reversal potential that lies within the dynamic range of SGN action potentials, developmental alteration of [Cl-]i, and hence the equilibrium potential for Cl- (ECl), transforms pre- to posthearing phenotype.

Original languageEnglish (US)
Pages (from-to)2575-2580
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number8
DOIs
StatePublished - Feb 24 2015

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Keywords

  • Action potentials
  • Calcium-activated chloride channels
  • Development
  • Hearing
  • Spiral ganglion neurons

ASJC Scopus subject areas

  • General

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