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

doi:10.18632/aging.102553

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).

Highlights

Previous studies have demonstrated distinct local domain-specific protein translation as a mechanism to confer multiple temporal and spatial neuronal functions [1]
We further demonstrate that the local functional synaptic alterations transition from hidden hearing loss (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
KNa1.1 and KNa1.2 have been localized in the medial nucleus of the trapezoid body (MNTB) in the auditory brainstem and shown to regulate spike timing [24, 25] and in peripheral neurons in the dorsal root ganglion (DRG), where they regulate nociceptive responses [23, 26, 27]

Summary

Introduction

Previous studies have demonstrated distinct local domain-specific protein translation as a mechanism to confer multiple temporal and spatial neuronal functions [1]. A standard threshold characterizes the early signs of ARHL, but there is a reduced suprathreshold www.aging-us.com amplitude of sound-elicited compound action potentials (AP), a reduction in peak I, and an increase in latency of the auditory brainstem response (ABR) waveform [8, 9]. The prevailing notion is that HHL begets additional auditory deficits and overt increases in audiometric threshold. These findings suggest that early but latent mechanisms underlying the development of ARHL if identified can be repressed, or reversed to prevent progression to overt HL. What are the mechanisms of HHL and the transition steps to overt HL? To date, structural dysfunction of the inner hair cell (IHC) synapse and transient primary AN demyelination have been demonstrated as two of the mechanisms of HHL [3, 8]

Methods

Results

Conclusion