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      Ribbon Synapses and Hearing Impairment in Mice After in utero Sevoflurane Exposure

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          Abstract

          Introduction

          In utero, exposure to sevoflurane (a commonly used inhalation anesthetic) can lead to hearing impairment in offspring mice, but the underlying impairment mechanism is not known.

          Materials and Methods

          Day-15 pregnant mice were treated with 2.5% sevoflurane for 2 h to investigate sevoflurane ototoxicity. Cochleae from offspring mice were harvested for hair-cell and ribbon-synapse assessments. Hearing in offspring mice was assessed at postnatal day 30 using an auditory brainstem-response (ABR) test. Cochlear-explant cultures from offspring mice were exposed to 2.5% sevoflurane for 6 h. Immediately after treatment, explants were assessed for hair-cell morphology, mitochondrial oxidative stress, and autophagy.

          Results

          In utero, sevoflurane exposure impaired hearing in the offspring is demonstrated by a decrease in ABR wave I amplitudes, a marker for ribbon-synapse functionality. Sevoflurane exposure caused no obvious damage to hair cells, but cochlear ribbon synapses were reduced in postnatal day 15 offspring, and partially recovered by postnatal day 30. Sevoflurane treatment also increased mitochondrial reactive-oxygen species stress and decreased autophagy in the cochlear explants.

          Conclusion

          These results suggest that oxidative stress and reduced autophagy may underly ribbon-synapse involvement in sevoflurane-induced hearing loss.

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          Most cited references 29

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          Transmitter release at the hair cell ribbon synapse.

          Neurotransmitters are released continuously at ribbon synapses in the retina and cochlea. Notably, a single ribbon synapse of inner hair cells provides the entire input to each cochlear afferent fiber. We investigated hair cell transmitter release in the postnatal rat cochlea by recording excitatory postsynaptic currents (EPSCs) from afferent boutons directly abutting the ribbon synapse. EPSCs were carried by rapidly gating AMPA receptors. EPSCs were clustered in time, indicating the possibility of coordinate release. Amplitude distributions of spontaneous EPSCs were highly skewed, peaking at 0.4 nS and ranging up to 20 times larger. Hair cell depolarization increased EPSC frequency up to 150 Hz without altering the amplitude distribution. We propose that the ribbon synapse operates by multivesicular release, possibly to achieve high-frequency transmission.
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            Neurotrophin-3 regulates ribbon synapse density in the cochlea and induces synapse regeneration after acoustic trauma

            Neurotrophin-3 (Ntf3) and brain derived neurotrophic factor (Bdnf) are critical for sensory neuron survival and establishment of neuronal projections to sensory epithelia in the embryonic inner ear, but their postnatal functions remain poorly understood. Using cell-specific inducible gene recombination in mice we found that, in the postnatal inner ear, Bbnf and Ntf3 are required for the formation and maintenance of hair cell ribbon synapses in the vestibular and cochlear epithelia, respectively. We also show that supporting cells in these epithelia are the key endogenous source of the neurotrophins. Using a new hair cell CreERT line with mosaic expression, we also found that Ntf3's effect on cochlear synaptogenesis is highly localized. Moreover, supporting cell-derived Ntf3, but not Bbnf, promoted recovery of cochlear function and ribbon synapse regeneration after acoustic trauma. These results indicate that glial-derived neurotrophins play critical roles in inner ear synapse density and synaptic regeneration after injury. DOI: http://dx.doi.org/10.7554/eLife.03564.001
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              Autophagy attenuates noise-induced hearing loss by reducing oxidative stress.

              Reactive oxygen species play a dual role in mediating both cell stress and defense pathways. Here, we used pharmacological manipulations and siRNA silencing to investigate the relationship between autophagy and oxidative stress under conditions of noise-induced temporary, permanent, and severe permanent auditory threshold shifts (temporary threshold shift [TTS], permanent threshold shift [PTS], and severe PTS [sPTS], respectively) in adult CBA/J mice.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                08 July 2020
                2020
                : 14
                : 2685-2693
                Affiliations
                [1 ]Department of Anesthesiology, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University , Shanghai 200031, People’s Republic of China
                [2 ]Research Center, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University , Shanghai 200031, People’s Republic of China
                [3 ]Department of Otorhinolaryngology, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University , Shanghai 200031, People’s Republic of China
                Author notes
                Correspondence: Huiqian Yu Department of Otorhinolaryngology, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University , Shanghai200031, People’s Republic of ChinaTel +86-21-64377134Fax +86-21-64373416 Email yhq925@163.com
                Xia Shen Department of Anesthesiology, Shanghai Eye, Ear, Nose, and Throat Hospital, Fudan University , Shanghai200031, People’s Republic of ChinaTel +86-21-64377134Fax +86-21-64373416 Email zlsx@yahoo.com
                [*]

                These authors contributed equally to this work

                Article
                253031
                10.2147/DDDT.S253031
                7354911
                © 2020 Yuan et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, References: 34, Pages: 9
                Categories
                Original Research

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