The local translation of KNa in dendritic projections of auditory neurons and the roles of KNa in the transition from hidden to overt hearing loss

Jeong Han Lee, Mincheol Kang, Seojin Park, Maria C. Perez-Flores, Xiao Dong Zhang, Wenying Wang, Michael Anne Gratton, Nipavan Chiamvimonvat, Ebenezer N Yamoah

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations

Abstract

Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that Na+-activated K+ (KNa) mRNA and channel proteins are distinctly and locally expressed in dendritic projections of primary ANs and genetic deletion of KNa channels (Kcnt1 and Kcnt2) results in the loss of proper AN synaptic function, characterized as HHL, without structural synaptic alterations. We further demonstrate that the local functional synaptic alterations transition from HHL to increased hearing-threshold, which entails changes in global Ca2+ homeostasis, activation of caspases 3/9, impaired regulation of inositol triphosphate receptor 1 (IP3R1), and apoptosis-mediated neurodegeneration. Thus, the present study demonstrates how local synaptic dysfunction results in an apparent latent pathological phenotype (HHL) and, if undetected, can lead to overt HL. It also highlights, for the first time, that HHL can precede structural synaptic dysfunction and AN demyelination. The stepwise cellular mechanisms from HHL to canonical HL are revealed, providing a platform for intervention to prevent lasting and irreversible age-related hearing loss (ARHL).

Original languageEnglish (US)
Pages (from-to)11541-11564
Number of pages24
JournalAging
Volume11
Issue number23
DOIs
StatePublished - Jan 1 2019

Keywords

  • Age-related hearing loss
  • Auditory neurons
  • Axonal protein translation
  • Hearing loss
  • Potassium channels

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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