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      Sodium-activated potassium channels shape peripheral auditory function and activity of the primary auditory neurons in mice

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          Abstract

          Potassium (K +) channels shape the response properties of neurons. Although enormous progress has been made to characterize K + channels in the primary auditory neurons, the molecular identities of many of these channels and their contributions to hearing in vivo remain unknown. Using a combination of RNA sequencing and single molecule fluorescent in situ hybridization, we localized expression of transcripts encoding the sodium-activated potassium channels K Na1.1 (SLO2.2/Slack) and K Na1.2 (SLO2.1/Slick) to the primary auditory neurons (spiral ganglion neurons, SGNs). To examine the contribution of these channels to function of the SGNs in vivo, we measured auditory brainstem responses in K Na1.1/1.2 double knockout (DKO) mice. Although auditory brainstem response (wave I) thresholds were not altered, the amplitudes of suprathreshold responses were reduced in DKO mice. This reduction in amplitude occurred despite normal numbers and molecular architecture of the SGNs and their synapses with the inner hair cells. Patch clamp electrophysiology of SGNs isolated from DKO mice displayed altered membrane properties, including reduced action potential thresholds and amplitudes. These findings show that K Na1 channel activity is essential for normal cochlear function and suggest that early forms of hearing loss may result from physiological changes in the activity of the primary auditory neurons.

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          Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline.

          Aging listeners experience greater difficulty understanding speech in adverse listening conditions and exhibit degraded temporal resolution, even when audiometric thresholds are normal. When threshold evidence for peripheral involvement is lacking, central and cognitive factors are often cited as underlying performance declines. However, previous work has uncovered widespread loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with recovered thresholds and no hair cell loss (Kujawa and Liberman 2009). Here, we characterize age-related cochlear synaptic and neural degeneration in CBA/CaJ mice never exposed to high-level noise. Cochlear hair cell and neuronal function was assessed via distortion product otoacoustic emissions and auditory brainstem responses, respectively. Immunostained cochlear whole mounts and plastic-embedded sections were studied by confocal and conventional light microscopy to quantify hair cells, cochlear neurons, and synaptic structures, i.e., presynaptic ribbons and postsynaptic glutamate receptors. Cochlear synaptic loss progresses from youth (4 weeks) to old age (144 weeks) and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts. Cochlear nerve loss parallels the synaptic loss, after a delay of several months. Key functional clues to the synaptopathy are available in the neural response; these can be accessed noninvasively, enhancing the possibilities for translation to human clinical characterization.
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            Noise-induced cochlear neuropathy is selective for fibers with low spontaneous rates.

            Acoustic overexposure can cause a permanent loss of auditory nerve fibers without destroying cochlear sensory cells, despite complete recovery of cochlear thresholds (Kujawa and Liberman 2009), as measured by gross neural potentials such as the auditory brainstem response (ABR). To address this nominal paradox, we recorded responses from single auditory nerve fibers in guinea pigs exposed to this type of neuropathic noise (4- to 8-kHz octave band at 106 dB SPL for 2 h). Two weeks postexposure, ABR thresholds had recovered to normal, while suprathreshold ABR amplitudes were reduced. Both thresholds and amplitudes of distortion-product otoacoustic emissions fully recovered, suggesting recovery of hair cell function. Loss of up to 30% of auditory-nerve synapses on inner hair cells was confirmed by confocal analysis of the cochlear sensory epithelium immunostained for pre- and postsynaptic markers. In single fiber recordings, at 2 wk postexposure, frequency tuning, dynamic range, postonset adaptation, first-spike latency and its variance, and other basic properties of auditory nerve response were all completely normal in the remaining fibers. The only physiological abnormality was a change in population statistics suggesting a selective loss of fibers with low- and medium-spontaneous rates. Selective loss of these high-threshold fibers would explain how ABR thresholds can recover despite such significant noise-induced neuropathy. A selective loss of high-threshold fibers may contribute to the problems of hearing in noisy environments that characterize the aging auditory system.
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              Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms.

              Common causes of hearing loss in humans - exposure to loud noise or ototoxic drugs and aging - often damage sensory hair cells, reflected as elevated thresholds on the clinical audiogram. Recent studies in animal models suggest, however, that well before this overt hearing loss can be seen, a more insidious, but likely more common, process is taking place that permanently interrupts synaptic communication between sensory inner hair cells and subsets of cochlear nerve fibers. The silencing of affected neurons alters auditory information processing, whether accompanied by threshold elevations or not, and is a likely contributor to a variety of perceptual abnormalities, including speech-in-noise difficulties, tinnitus and hyperacusis. Work described here will review structural and functional manifestations of this cochlear synaptopathy and will consider possible mechanisms underlying its appearance and progression in ears with and without traditional 'hearing loss' arising from several common causes in humans.
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                Author and article information

                Contributors
                s.pyott@umcg.nl
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                22 February 2019
                22 February 2019
                2019
                : 9
                : 2573
                Affiliations
                [1 ]ISNI 0000 0000 9558 4598, GRID grid.4494.d, University of Groningen, University Medical Center Groningen, Groningen, Department of Otorhinolaryngology and Head/Neck Surgery, ; 9713GZ Groningen, The Netherlands
                [2 ]ISNI 0000 0004 1936 914X, GRID grid.266818.3, Department of Physiology and Cell Biology, Program in Communication and Sensory Sciences, School of Medicine, , University of Nevada Reno, ; Reno, NV 89557 USA
                [3 ]ISNI 0000 0004 1937 0060, GRID grid.24434.35, University of Nebraska Lincoln, Department of Special Education and Communication Disorders, ; 304B Barkley Memorial Center, Lincoln, NE 68583 USA
                [4 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Departments of Otorhinolaryngology Head and Neck Surgery and Anesthesiology, , Washington University School of Medicine, ; St. Louis, MO 63110 USA
                Author information
                http://orcid.org/0000-0002-6485-588X
                http://orcid.org/0000-0003-3611-2939
                Article
                39119
                10.1038/s41598-019-39119-z
                6384918
                30796290
                54a08f8d-9a7f-424c-a452-ff3fdd6f709e
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 October 2018
                : 17 January 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/100006955, U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER);
                Award ID: P01 AG051443
                Award ID: R01 DC015135
                Award ID: R01 DC016099
                Award Recipient :
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