Early functional alterations in membrane properties and neuronal degeneration are hallmarks of progressive hearing loss in NOD mice

Jeong Han Lee,Wenying Wang,Nipavan Chiamvimonvat,Leighton Izu,Michael Anne Gratton,Seojin Park,Hyo Jeong Kim,Maria C Perez-Flores,Ebenezer N Yamoah

doi:10.1038/s41598-019-48376-x

Jeong Han Lee, Wenying Wang + Show 7 more

Open Access

https://doi.org/10.1038/s41598-019-48376-x

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Abstract

Presbycusis or age-related hearing loss (ARHL) is the most common sensory deficit in the human population. A substantial component of the etiology stems from pathological changes in sensory and non-sensory cells in the cochlea. Using a non-obese diabetic (NOD) mouse model, we have characterized changes in both hair cells and spiral ganglion neurons that may be relevant for early signs of age-related hearing loss (ARHL). We demonstrate that hair cell loss is preceded by, or in parallel with altered primary auditory neuron functions, and latent neurite retraction at the hair cell-auditory neuron synapse. The results were observed first in afferent inner hair cell synapse of type I neurites, followed by type II neuronal cell-body degeneration. Reduced membrane excitability and loss of postsynaptic densities were some of the inaugural events before any outward manifestation of hair bundle disarray and hair cell loss. We have identified profound alterations in type I neuronal membrane properties, including a reduction in membrane input resistance, prolonged action potential latency, and a decrease in membrane excitability. The resting membrane potential of aging type I neurons in the NOD, ARHL model, was significantly hyperpolarized, and analyses of the underlying membrane conductance showed a significant increase in K+ currents. We propose that attempts to alleviate some forms of ARHL should include early targeted primary latent neural degeneration for effective positive outcomes.

Highlights

Age-related hearing loss (ARHL) is the prevalent form of sensory deficit worldwide
Using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) assessment, we examined the longitudinal progression of changes in hearing thresholds in 4–12-week old ICR/vHaJ and non-obese diabetic (NOD).CB17-Prkdcscid/J mice, referred to as ICR control and NOD mice, respectively
The loss of outer HC (OHC) may contribute towards the increased ABR threshold

Summary

Introduction

Age-related hearing loss (ARHL) is the prevalent form of sensory deficit worldwide. The disease remains less understood, owing to the apparent late-onset phenotype and confounding factors, such as ototoxic drugs, noise trauma, and genetic pre-dispositions[1,2,3]. Cdh23ahl and ahl[2], are responsible for hair cell (HC) loss and an unidentified inner ear pathology, respectively[14,15,16] These studies have provided a detailed characterization of the pathology of the cochlea in ARHL, but the functional neural mechanisms remain largely unknown. Www.nature.com/scientificreports neuronal degeneration occurs secondary to HC loss[14]. Recent reports have demonstrated that degeneration of afferent neurites may precede HC loss in NIHL models[17,24,25], raising the possibility that there are early but “silent” neural mechanisms associated with NIHL that could be exploited to alleviate the long-term effects of the disease. We used the NOD mouse model to study mechanisms of early hearing loss.

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