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New insights into cochlear sound encoding

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F1000Research

inner hair cell, synaptic ribbon, otoferlin

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      Abstract

      The inner ear uses specialized synapses to indefatigably transmit sound information from hair cells to spiral ganglion neurons at high rates with submillisecond precision. The emerging view is that hair cell synapses achieve their demanding function by employing an unconventional presynaptic molecular composition. Hair cell active zones hold the synaptic ribbon, an electron-dense projection made primarily of RIBEYE, which tethers a halo of synaptic vesicles and is thought to enable a large readily releasable pool of vesicles and to contribute to its rapid replenishment. Another important presynaptic player is otoferlin, coded by a deafness gene, which assumes a multi-faceted role in vesicular exocytosis and, when disrupted, causes auditory synaptopathy. A functional peculiarity of hair cell synapses is the massive heterogeneity in the sizes and shapes of excitatory postsynaptic currents. Currently, there is controversy as to whether this reflects multiquantal release with a variable extent of synchronization or uniquantal release through a dynamic fusion pore. Another important question in the field has been the precise mechanisms of coupling presynaptic Ca 2+ channels and vesicular Ca 2+ sensors. This commentary provides an update on the current understanding of sound encoding in the cochlea with a focus on presynaptic mechanisms.

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      Most cited references 78

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      Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels.

      Voltage-gated L-type Ca2+ channels (LTCCs) containing a pore-forming alpha1D subunit (D-LTCCs) are expressed in neurons and neuroendocrine cells. Their relative contribution to total L-type Ca2+ currents and their physiological role and significance as a drug target remain unknown. Therefore, we generated D-LTCC deficient mice (alpha1D-/-) that were viable with no major disturbances of glucose metabolism. alpha1D-/-mice were deaf due to the complete absence of L-type currents in cochlear inner hair cells and degeneration of outer and inner hair cells. In wild-type controls, D-LTCC-mediated currents showed low activation thresholds and slow inactivation kinetics. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia) in alpha1D-/- mice. We conclude that alpha1D can form LTCCs with negative activation thresholds essential for normal auditory function and control of cardiac pacemaker activity.
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        Nanodomain coupling between Ca²⁺ channels and sensors of exocytosis at fast mammalian synapses.

        The physical distance between presynaptic Ca(2+) channels and the Ca(2+) sensors that trigger exocytosis of neurotransmitter-containing vesicles is a key determinant of the signalling properties of synapses in the nervous system. Recent functional analysis indicates that in some fast central synapses, transmitter release is triggered by a small number of Ca(2+) channels that are coupled to Ca(2+) sensors at the nanometre scale. Molecular analysis suggests that this tight coupling is generated by protein-protein interactions involving Ca(2+) channels, Ca(2+) sensors and various other synaptic proteins. Nanodomain coupling has several functional advantages, as it increases the efficacy, speed and energy efficiency of synaptic transmission.
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          Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse.

          The auditory inner hair cell (IHC) ribbon synapse operates with an exceptional temporal precision and maintains a high level of neurotransmitter release. However, the molecular mechanisms underlying IHC synaptic exocytosis are largely unknown. We studied otoferlin, a predicted C2-domain transmembrane protein, which is defective in a recessive form of human deafness. We show that otoferlin expression in the hair cells correlates with afferent synaptogenesis and find that otoferlin localizes to ribbon-associated synaptic vesicles. Otoferlin binds Ca(2+) and displays Ca(2+)-dependent interactions with the SNARE proteins syntaxin1 and SNAP25. Otoferlin deficient mice (Otof(-/-)) are profoundly deaf. Exocytosis in Otof(-/-) IHCs is almost completely abolished, despite normal ribbon synapse morphogenesis and Ca(2+) current. Thus, otoferlin is essential for a late step of synaptic vesicle exocytosis and may act as the major Ca(2+) sensor triggering membrane fusion at the IHC ribbon synapse.
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            Author and article information

            Affiliations
            [1 ]Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany
            [2 ]Auditory Neuroscience Group, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany
            [3 ]Synaptic Nanophysiology Group, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany
            [4 ]Auditory Neuroscience and Optogenetics Group, German Primate Center, Göttingen, Germany
            Author notes

            Competing interests: The authors declare that they have no competing interests.

            Journal
            F1000Res
            F1000Res
            F1000Research
            F1000Research
            F1000Research (London, UK )
            2046-1402
            26 August 2016
            2016
            : 5
            5007750 10.12688/f1000research.8924.1
            Copyright: © 2016 Moser T and Vogl C

            This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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            Funding
            This work was supported by grants from the German Research Foundation through the Collaborative Research Center 889 and the Leibniz Program (to TM).
            Categories
            Review
            Articles
            Membranes & Sorting
            Neuronal & Glial Cell Biology
            Neuronal Signaling Mechanisms
            Sensory Systems

            otoferlin, synaptic ribbon, inner hair cell

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