Auditory Neuropathy after Damage to Cochlear Spiral Ganglion Neurons in Mice Resulting from Conditional Expression of Diphtheria Toxin Receptors

Haolai Pan,Shankai Yin,Jiping Wang,Jian Wang,Yanyan Huang,Qiang Song,Renjie Chai

doi:10.1038/s41598-017-06600-6

Abstract

Auditory neuropathy (AN) is a hearing disorder characterized by normal cochlear amplification to sound but poor temporal processing and auditory perception in noisy backgrounds. These deficits likely result from impairments in auditory neural synchrony; such dyssynchrony of the neural responses has been linked to demyelination of auditory nerve fibers. However, no appropriate animal models are currently available that mimic this pathology. In this study, Cre-inducible diphtheria toxin receptor (iDTR+/+) mice were cross-mated with mice containing Cre (Bhlhb5-Cre+/−) specific to spiral ganglion neurons (SGNs). In double-positive offspring mice, the injection of diphtheria toxin (DT) led to a 30–40% rate of death for SGNs, but no hair cell damage. Demyelination types of pathologies were observed around the surviving SGNs and their fibers, many of which were distorted in shape. Correspondingly, a significant reduction in response synchrony to amplitude modulation was observed in this group of animals compared to the controls, which had a Cre− genotype. Taken together, our results suggest that SGN damage following the injection of DT in mice with Bhlhb5-Cre+/− and iDTR+/− is likely to be a good AN model of demyelination.

Highlights

Auditory neuropathy (AN) is a hearing disorder characterized as having normal cochlear microphonic (CM) potentials and otoacoustic emissions (OAEs), but largely reduced or missing auditory brainstem responses (ABRs)
The impact of spiral ganglion neurons (SGNs) death induced by diphtheria toxin (DT) application on auditory function was evaluated in terms of the ABR threshold, compound action potential (CAP) input/output functions in response to tone-bursts, and CAP responses to the amplitude modulation (AM) signals
Hair cells were not damaged in this model and the auditory sensitivity remained unchanged; 3

Summary

Introduction

Auditory neuropathy (AN) is a hearing disorder characterized as having normal cochlear microphonic (CM) potentials and otoacoustic emissions (OAEs), but largely reduced or missing auditory brainstem responses (ABRs). Since the major functional disorder in human subjects with AN is a lack of synchrony in signal processing[10], demyelination of auditory nerve fibers (ANFs) is predicted to be a major pathology in AN. No such damage has been identified as the core pathology for AN in human subjects except where AN is part of hereditary disorders[8]. Selective damage to IHCs and consequent degeneration of SGNs were observed in chinchillas using carboplatin This unique pathology was initially reported in the early 1990s; it was hoped that it would produce a model for AN12.

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Conclusion