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      Burst activity and ultrafast activation kinetics of Ca V1.3 Ca 2+ channels support presynaptic activity in adult gerbil hair cell ribbon synapses

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          Abstract

          Auditory information transfer to afferent neurons relies on precise triggering of neurotransmitter release at the inner hair cell (IHC) ribbon synapses by Ca 2+ entry through Ca V1.3 Ca 2+ channels. Despite the crucial role of Ca V1.3 Ca 2+ channels in governing synaptic vesicle fusion, their elementary properties in adult mammals remain unknown. Using near-physiological recording conditions we investigated Ca 2+ channel activity in adult gerbil IHCs. We found that Ca 2+ channels are partially active at the IHC resting membrane potential (−60 mV). At −20 mV, the large majority (>70%) of Ca 2+ channel first openings occurred with an estimated delay of about 50 μs in physiological conditions, with a mean open time of 0.5 ms. Similar to other ribbon synapses, Ca 2+ channels in IHCs showed a low mean open probability (0.21 at −20 mV), but this increased significantly (up to 0.91) when Ca 2+ channel activity switched to a bursting modality. We propose that IHC Ca 2+ channels are sufficiently rapid to transmit fast signals of sound onset and support phase-locking. Short-latency Ca 2+ channel opening coupled to multivesicular release would ensure precise and reliable signal transmission at the IHC ribbon synapse.

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          Most cited references37

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          Release probability of hippocampal glutamatergic terminals scales with the size of the active zone

          Cortical synapses display remarkable structural, molecular and functional heterogeneity. Our knowledge regarding the relationship between the ultrastructural and functional parameters is still fragmented. Here we asked how the release probability and presynaptic [Ca2+] transients relate to the ultrastructure of rat hippocampal glutamatergic axon terminals. Two-photon Ca2+ imaging-derived optical quantal analysis and correlated electron microscopic reconstructions revealed a tight correlation between the release probability and the active zone area. The peak amplitude of [Ca2+] transients in single boutons also positively correlated with the active zone area. Freeze-fracture immunogold labeling revealed that the voltage-gated Ca2+ channel subunit Cav2.1 and the presynaptic protein Rim1/2 are confined to the active zone and their numbers scale linearly with the active zone area. Gold particles for Cav2.1 showed a nonrandom distribution within the active zones. Our results demonstrate that the number of several active zone proteins, including presynaptic Ca2+ channels, docked vesicles and the release probability scales linearly with the active zone area.
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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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              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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                Author and article information

                Journal
                J Physiol
                J. Physiol. (Lond.)
                tjp
                The Journal of Physiology
                Blackwell Publishing Ltd (Oxford, UK )
                0022-3751
                1469-7793
                15 August 2013
                27 May 2013
                : 591
                : 16
                : 3811-3820
                Affiliations
                [1 ]Department of Biomedical Science, University of Sheffield Sheffield, S10 2TN, UK
                [2 ]Department of Biology and Biotechnology, University of Pavia Pavia, 27100, Italy
                [3 ]Department of Otolaryngology, THRC, Laboratory of Molecular Physiology of Hearing, University of Tübingen D-72076 Tübingen, Germany
                Author notes
                W. Marcotti: Department of Biomedical Science, University of Sheffield, Sheffield, S10 2TN, UK. Email: w.marcotti@ 123456sheffield.ac.uk
                Article
                10.1113/jphysiol.2013.251272
                3764630
                23713031
                31852878-8740-47a5-8179-cb864f7eb807
                © 2013 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                : 16 January 2013
                : 23 May 2013
                Categories
                Neuroscience: Cellular/Molecular

                Human biology
                Human biology

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