Highlights d TMC1/2 cannot form functional mechanotransduction channels in hair cells without TMIE d TMIE is a subunit of the mechanotransduction channel of cochlear hair cells d TMIE mutations affect pore properties such as conductance and ion selectivity d TMIE binds PIP 2 , and deafness mutations affect PIP 2 binding and transduction

The early onset of peripheral deafness profoundly alters the functional maturation of the central auditory system. A prolonged exposure to an artificial acoustic environment has a similar disruptive influence. These observations establish the importance of normal patterns of sound-driven activity during the initial stages of auditory development. The present study was designed to address the role of cochlear gain control during these activity-dependent developmental processes. It was hypothesized that the regulation of auditory nerve activity by the medial olivocochlear system (MOCS) would preserve normal development when the immature auditory system was challenged by continuous background noise. To test this hypothesis, knock-out mice lacking MOCS feedback were reared in noisy or quiet environments and then evaluated with behavioral paradigms for auditory processing deficits. Relative to wild-type controls, noise-reared knock-out mice showed a decreased ability to process rapid acoustic events. Additional anatomical and physiological assessments linked these perceptual deficits to synaptic defects in the auditory brainstem that shared important features with human auditory neuropathy. Our findings offer a new perspective on the potentially damaging effects of environmental noise and how these risks are ameliorated by the protective role of MOCS feedback.

Non-technical summary Localization of sound sources in the azimuth, which makes use of interaural differences in timing and/or intensity of acoustic signals, is of vital importance for most mammals. Using the small differences in time of arrival and/or intensity at the two ears requires that propagation of electric pulses in the auditory system be temporally precise. In this study, we found that elimination of GluA4, a protein particularly abundant in auditory cells, significantly impairs their ability to faithfully transmit electric signals, leading to profound deficits in auditory responses to sound stimuli in mice. Therefore, we conclude that GluA4 is indispensable for enabling information flow with high fidelity in the auditory circuitry. Our work has identified GluA4 as a potential molecular candidate involved in human hearing deficits and disorders.Abstract Fast excitatory synaptic transmission in central synapses is mediated primarily by AMPA receptors (AMPARs), which are heteromeric assemblies of four subunits, GluA1-4. Among these subunits, rapidly gating GluA3/4 appears to be the most abundantly expressed to enable neurotransmission with submillisecond precision at fast rates in subsets of central synapses. However, neither definitive identification of the molecular substrate for native AMPARs in these neurons, nor their hypothesized functional roles in vivo has been unequivocally demonstrated, largely due to lack of specific antagonists. Using GluA3 or GluA4 knockout (KO) mice, we investigated these issues at the calyx of Held synapse, which is known as a high-fidelity synapse involved in sound localization. Patch-clamp recordings from postsynaptic neurons showed that deletion of GluA4 significantly slowed the time course of both evoked and miniature AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs), reduced their amplitude, and exacerbated AMPAR desensitization and short-term depression (STD). Surprisingly, presynaptic release probability was also elevated, contributing to severe STD at GluA4-KO synapses. In contrast, only marginal changes in AMPAR-EPSCs were found in GluA3-KO mice. Furthermore, independent of changes in intrinsic excitability of postsynaptic neurons, deletion of GluA4 markedly reduced synaptic drive and increased action potential failures during high-frequency activity, leading to profound deficits in specific components of the auditory brainstem responses associated with synchronized spiking in the calyx of Held synapse and other related neurons in vivo. These observations identify GluA4 as the main determinant for fast synaptic response, indispensable for driving high-fidelity neurotransmission and conveying precise temporal information.

Efferent innervation of the cochlea undergoes extensive modification early in development, but it is unclear if efferent synapses are modified by age, hearing loss, or both. Structural alterations in the cochlea affecting information transfer from the auditory periphery to the brain may contribute to age-related hearing deficits. We investigated changes to efferent innervation in the vicinity of inner hair cells (IHC) in young and old C57BL/6 mice using transmission electron microscopy to reveal increased efferent innervation of IHCs in older animals. Efferent contacts on IHCs contained focal pre-synaptic accumulations of small vesicles. Synaptic vesicle size and shape were heterogeneous. Postsynaptic cisterns were occasionally observed. Increased IHC efferent innervation was associated with a smaller number of afferent synapses per IHC, increased outer hair cell loss, and elevated auditory brainstem response thresholds. Efferent axons also formed synapses on afferent dendrites but with a reduced prevalence in older animals. Age-related reduction of afferent activity may engage signaling pathways that support the return to an immature state of efferent innervation of the cochlea.