Auditory neuropathy--neural and synaptic mechanisms.

Tobias Moser,Arnold Starr

doi:10.1038/nrneurol.2016.10

Abstract

Sensorineural hearing impairment is the most common form of hearing loss, and encompasses pathologies of the cochlea and the auditory nerve. Hearing impairment caused by abnormal neural encoding of sound stimuli despite preservation of sensory transduction and amplification by outer hair cells is known as 'auditory neuropathy'. This term was originally coined for a specific type of hearing impairment affecting speech comprehension beyond changes in audibility: patients with this condition report that they "can hear but cannot understand". This type of hearing impairment can be caused by damage to the sensory inner hair cells (IHCs), IHC ribbon synapses or spiral ganglion neurons. Human genetic and physiological studies, as well as research on animal models, have recently shown that disrupted IHC ribbon synapse function--resulting from genetic alterations that affect presynaptic glutamate loading of synaptic vesicles, Ca(2+) influx, or synaptic vesicle exocytosis--leads to hearing impairment termed 'auditory synaptopathy'. Moreover, animal studies have demonstrated that sound overexposure causes excitotoxic loss of IHC ribbon synapses. This mechanism probably contributes to hearing disorders caused by noise exposure or age-related hearing loss. This Review provides an update on recently elucidated sensory, synaptic and neural mechanisms of hearing impairment, their corresponding clinical findings, and discusses current rehabilitation strategies as well as future therapies.

Highlights

Impaired sound encoding in auditory neuropathiesFor decades, research into hearing loss focused on dys function or loss of sensory hair cells and failure of coch lear ion homeostasis as key mechanisms of sensorineuralNATURE REVIEWS | NEUROLOGY
This type of hearing impairment can be caused by damage to the sensory inner hair cells (IHCs), IHC ribbon synapses or spiral ganglion neurons
We provide a short guide to clinical diagnosis of auditory neuropathy, with a focus on appropriate physiological and psychophysical tests

Summary

Key points

Auditory neuropathy impairs speech comprehension severely, beyond the extent that would be expected on the basis of increased threshold of audibility. D | In an individual with an auditory synaptopathy caused by OTOF mutation, MPs are intact; e | SPs are present, but CAPs are not detectable even for 120 dB clicks, indicating intact outer and inner hair cell sound transduction but lack of synchronous SGN activation, most likely caused by failure of synaptic transmission owing to dysfunctional otoferlin protein. In the IHCs of these mutant mice, exocyto sis was normal in response to short stimuli, but much reduced as soon as vesicle replenishment was required at the release sites of the active zone[19] This defect in vesicle replenishment was shown to nearly abolish sound encoding at the hair cell synapse in vivo. Experiments on Cabp[2] mutant mice are needed to fully comprehend the effects of CaBP2 disruption on the hair cell Ca2+ influx and synaptic sound encoding

II III eABR

Findings

Conclusions