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Using recordings from mature gerbils, we report here a surprisingly strong block of exocytosis by the slow Ca<jats:sup>2+<\/jats:sup>buffer EGTA (10 mM) in basal hair cells tuned to high frequencies (\u223c30 kHz). In addition, using recordings from gerbil, mouse, and bullfrog auditory organs, we find that the spatial coupling between Ca<jats:sup>2+<\/jats:sup>influx and exocytosis changes from nanodomain in low-frequency tuned hair cells (\u223c&lt;2 kHz) to progressively more microdomain in high-frequency cells (\u223c&gt;2 kHz). Hair cell synapses have thus developed remarkable frequency-dependent tuning of exocytosis: accurate low-latency encoding of onset and offset of sound intensity in the cochlea's base and submillisecond encoding of membrane receptor potential fluctuations in the apex for precise phase-locking to sound signals. We also found that synaptic vesicle pool recovery from depletion was sensitive to high concentrations of EGTA, suggesting that intracellular Ca<jats:sup>2+<\/jats:sup>buffers play an important role in vesicle recruitment in both low- and high-frequency hair cells. In conclusion, our results indicate that microdomain coupling is important for exocytosis in high-frequency hair cells, suggesting a novel hypothesis for why these cells are more susceptible to sound-induced damage than low-frequency cells; high-frequency inner hair cells must have a low Ca<jats:sup>2+<\/jats:sup>buffer capacity to sustain exocytosis, thus making them more prone to Ca<jats:sup>2+<\/jats:sup>-induced cytotoxicity.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>In the inner ear, sensory hair cells signal reception of sound. They do this by converting the sound-induced movement of their hair bundles present at the top of these cells, into an electrical current. This current depolarizes the hair cell and triggers the calcium-induced release of the neurotransmitter glutamate that activates the postsynaptic auditory fibers. The speed and precision of this process enables the brain to perceive the vital components of sound, such as frequency and intensity. We show that the coupling strength between calcium channels and the exocytosis calcium sensor at inner hair cell synapses changes along the mammalian cochlea such that the timing and\/or intensity of sound is encoded with high precision.<\/jats:p>","DOI":"10.1523\/jneurosci.2867-16.2017","type":"journal-article","created":{"date-parts":[[2017,2,3]],"date-time":"2017-02-03T02:10:30Z","timestamp":1486087830000},"page":"2471-2484","source":"Crossref","is-referenced-by-count":58,"title":["The Coupling between Ca<sup>2+<\/sup>Channels and the Exocytotic Ca<sup>2+<\/sup>Sensor at Hair Cell Ribbon Synapses Varies Tonotopically along the Mature Cochlea"],"prefix":"10.1523","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3355-650X","authenticated-orcid":false,"given":"Stuart 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