Synaptic Release Potentiation at Aging Auditory Ribbon Synapses.

Thibault Peineau,Susanna Pietropaolo,Didier Dulon,Séverin Belleudy,Yohan Bouleau

doi:10.3389/fnagi.2021.756449

Abstract

Age-related hidden hearing loss is often described as a cochlear synaptopathy that results from a progressive degeneration of the inner hair cell (IHC) ribbon synapses. The functional changes occurring at these synapses during aging are not fully understood. Here, we characterized this aging process in IHCs of C57BL/6J mice, a strain which is known to carry a cadherin-23 mutation and experiences early hearing loss with age. These mice, while displaying a large increase in auditory brainstem thresholds due to 50% loss of IHC synaptic ribbons at middle age (postnatal day 365), paradoxically showed enhanced acoustic startle reflex suggesting a hyperacusis-like response. The auditory defect was associated with a large shrinkage of the IHCs' cell body and a drastic enlargement of their remaining presynaptic ribbons which were facing enlarged postsynaptic AMPAR clusters. Presynaptic Ca2+ microdomains and the capacity of IHCs to sustain high rates of exocytosis were largely increased, while on the contrary the expression of the fast-repolarizing BK channels, known to negatively control transmitter release, was decreased. This age-related synaptic plasticity in IHCs suggested a functional potentiation of synaptic transmission at the surviving synapses, a process that could partially compensate the decrease in synapse number and underlie hyperacusis.

Highlights

Age-related hearing loss (ARHL or presbycusis) is the most prevalent form of sensory disability in human populations and adversely affects the quality of life of many elderly individuals
Counting hair cells on surface preparations of organs of Corti from these P365 mice, in the mid-cochlea region (8–16 kHz), indicated only a moderate loss of Outer Hair Cell (OHC) and inner hair cell (IHC), in good agreement with the study of Zachary and Fuchs (Zachary and Fuchs, 2015). This moderate loss of OHCs suggested that the profound hearing loss occurring at P365 in C57BL/6J mice arose from additional factors than a simple alteration of the cochlear amplifier
The wave-I is known to result from the synchronous activity of the auditory nerve fibers and can provide an objective measure of ribbon synapses loss when measured at high sound intensity above 70 dB SPL

Summary

Introduction

Age-related hearing loss (ARHL or presbycusis) is the most prevalent form of sensory disability in human populations and adversely affects the quality of life of many elderly individuals. The development of ARHL has been generally considered to be associated with primary degeneration of cochlear hair cells, with secondary deafferentation associating degeneration of spiral ganglion neurons and ribbon synapses. Recent studies have resulted in a paradigm shift in the understanding of the early cause of ARHL (Kujawa and Liberman, 2015, 2019). During aging, hearing thresholds in the elderly often remain normal but speech intelligibility becomes hampered, especially in noisy environment. This pathology in the elderly is referred as hidden hearing loss and has been proposed to be caused in mice by an early loss of ribbon synapses contacting the inner hair cells (IHCs), well before any major loss of hair cells and spiral ganglion neurons (Stamataki et al, 2006). While glutamate excitotoxicity, resulting in nerve terminal swelling, has been proposed to play a role in the setting of noise-induced hearing

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