Finally, we show that AP-2 sorts its IHC-cargo otoferlin. Sustained strong stimulation led to accumulation of endosome-like vacuoles, fewer clathrin-coated endocytic intermediates, and vesicle depletion of the membrane-distal synaptic ribbon in AP-2μ-deficient IHCs, indicating a further role of AP-2μ in clathrin-dependent vesicle reformation on a timescale of many seconds. Sound-driven postsynaptic spiking was reduced in a use-dependent manner, and the altered interspike interval statistics suggested a slowed reloading of release sites. We show that hair cell-specific disruption of AP-2μ slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane-proximal vesicles and intact endocytic membrane retrieval. Here, we report that the endocytic adaptor protein 2μ (AP-2μ) is required for release site replenishment and hearing. Tel: +803 E-mail: Īctive zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. ‡ These authors contributed equally to this work.14 Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University of Göttingen, Göttingen, Germany.13 Molecular Biology of Cochlear Neurotransmission Group, InnerEarLab, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany.12 Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany.11 Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.10 Department of Molecular Structural Biology, Institute for Microbiology and Genetics, University of Göttingen, Göttingen, Germany.9 Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany.8 Bernstein Group Biophysics of Neural Computation, Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany.7 Auditory Systems Physiology Group, InnerEarLab, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany.6 Molecular Architecture of Synapses Group, Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany. 5 NeuroCure Cluster of Excellence & Collaborative Research Center 958, Freie Universität Berlin, Berlin, Germany.4 Leibniz Institut für Molekulare Pharmakologie (FMP), Berlin, Germany.3 Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.2 Collaborative Research Center 889, University of Göttingen, Göttingen, Germany.1 Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.
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