Mechanisms and consequences of auditory fatigue in auditory synaptopathy DFNB9

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Mutations in the OTOF gene in patients with auditory synaptopathy DFNB9 lead to auditory fatigue and deafness. However, patients can perceive rare sound stimuli presented in a quiet environment. In less severely affected cases, hearing thresholds are nearly normal but speech perception is very poor. The disease mechanism involves enhanced adaptation at the inner hair cell ribbon synapse due to a vesicle replenishment deficit. We now show that this specific defect of cochlear sound encoding can only partially be compensated centrally. We performed in vivo single neuron recordings in mouse mutants carrying the human relevant I515T point mutation in the Otof gene. In the anteroventral cochlear nucleus, cells detecting precise simultaneous spiking from several input neurons (Onset neurons, Bushy cells) were more severely affected than cells which integrate several inputs (multipolar cells) over a longer time window. In the inferior colliculus, there was a striking deficit in the encoding of amplitude modulated stimuli: the action potentials showed normal phase locking, but the spike rates were strongly reduced due to abnormal adaptation following the repetitive sound envelope peaks. In the more severly affected “pachanga” mouse, spiking could only be elicited by very slow stimulation. The reduction in the encoding of rapid fluctuations of stimulus intensity due to synaptic fatigue in inner hair cells explains the difficulties in speech perception in DFNB9 patients. A reduction of background sounds and of sound intensity in general may reduce the abnormal adaptation and promote speech perception. A psychophysical test for the detection of silent gaps in noise would be ideal for diagnosis. Publication History Publication Date: 23 April 2019 (online) © 2019. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/). Georg Thieme Verlag KG Stuttgart · New York

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