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Kinetics of Exocytosis and Endocytosis at the Cochlear Inner Hair Cell Afferent Synapse of the Mouse

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Kinetics of Exocytosis and Endocytosis at the Cochlear Inner Hair Cell Afferent Synapse of the Mouse Kinetics of exocytosis and endocytosis at the cochlear inner hair cell afferent synapse of the mouse Tobias Moser†‡ and Dirk Beutner‡ Department of Membrane Biophysics, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg, 37077 Goettingen, Germany; and Department of Otolaryngology, Goettingen University Medical School, Robert-Koch-Strasse, 37073 Goettingen, Germany Edited by A. James Hudspeth, The Rockefeller University, New York, NY, and approved November 22, 1999 (received for review October 4, 1999) Hearing in mammals relies on the highly synchronous synaptic indicator [EGTA, 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ- transfer between cochlear inner hair cells (IHCs) and the auditory tetraacetate (BAPTA), or FURA-2; Molecular Probes] as spec- nerve. We studied the presynaptic function of single mouse IHCs by ified in the figure legends. For perforated-patch experiments, monitoring membrane capacitance changes and voltage-gated amphotericin B (250 ␮g͞ml) was added. Changes in intracellular 2؉ 2ϩ 2ϩ Ca currents. Exocytosis initially occurred at a high rate but then Ca concentration ([Ca ]i) measured by FURA-2 fluorometry slowed down within a few milliseconds, despite nearly constant are expressed as the fluorescence ratio at 360- and 390-nm Ca2؉ influx. We interpret the observed secretory depression as excitation. Ca2ϩ currents showed a tendency to decrease with depletion of a readily releasable pool (RRP) of about 280 vesicles. age, possibly because of a higher susceptibility to damage by the These vesicles are probably docked close to Ca2؉ channels at the dissection of the older organs of Corti. To compensate for the ribbon-type active zones of the IHCs. Continued depolarization possible dissection-associated loss of Ca2ϩ channels, an elevated 2ϩ 2ϩ evoked slower exocytosis occurring at a nearly constant rate for at extracellular Ca concentration ([Ca ]e; 10 mM CaCl2) was least 1 s and depending on ‘‘long-distance’’ Ca2؉ signaling. Refill- used for all experiments except for those of Fig. 1b (2 mM ing of the RRP after depletion followed a biphasic time course and CaCl2). The extracellular solution further contained (in mM) 105 was faster than endocytosis. RRP depletion is discussed as a NaCl, 35 tetraethylammonium chloride (Pfaltz & Bauer), 2.8 mechanism for fast auditory adaptation. KCl, 1 MgCl2, 10 NaOH-Hepes, and 10 D-glucose (pH 7.2). Solution changes were achieved by bath exchange. IHCs were he inner hair cell (IHC) is the primary sensory cell of the stimulated electrically rather than mechanically, because Cm cochlea exciting the auditory nerve in response to incoming measurements require voltage clamp. Unless stated otherwise, a T Ϸ sound (reviewed in ref. 1). Deflections of the IHC’s stereocilia, resting period of 30 s was kept between depolarizations to caused by movements of the tectorial membrane and hair cells allow recovery of exocytosis. EPC-9 amplifiers (HEKA Elec- ͞ relative to each other, gate stereociliar mechanosensitive trans- tronics, Lambrecht Pfalz, Germany) controlled by PULSE soft- ducer channels. The transduction current depolarizes the cell, ware (HEKA Electronics) were used for measurements. All ϩ ϩ Ϫ thereby opening basolateral voltage-gated Ca2 and K chan- voltages were corrected for liquid junction potentials ( 10 mV). 2ϩ nels. The resulting Ca2ϩ influx at the ribbon-type active zones Ca current amplitudes were measured during the first 5 ms of triggers exocytosis of synaptic vesicles, which probably release the depolarization and are presented without leak correction. Ϫ Ϫ glutamate (2) onto glutamate receptors (3, 4) of the postsynaptic Cells with a holding current exceeding 40 pA at 80 mV were Ϯ auditory nerve fibers. There is little information about the excluded from analysis. Means are expressed SEM. presynaptic function of IHCs, because the small diameter of auditory nerve fibers in mammals hinders postsynaptic record- Capacitance Measurements. We measured Cm by using the ings. Assumptions about transmitter release have, therefore, Lindau–Neher technique (ref. 13; implemented in the software mainly been based on auditory nerve fiber spiking rate data (5) ‘‘lock-in’’ module of PULSE) combined with compensation of or on Furukawa’s classical recordings of postsynaptic potentials pipette and resting cell capacitances by the EPC-9 compensation NEUROBIOLOGY from goldfish (6). circuitries. A 1-kHz, 70-mV peak-to-peak sinusoid was applied at Ϫ To study the presynaptic function of mouse IHCs indepen- a dc holding potential of 80 mV. After depolarization, slow tail dently of postsynaptic recordings, we detected the exocytic currents were observed (see Fig. 1C Lower). Their reversal fusion and endocytic retrieval of synaptic vesicle membrane as potential was estimated as x-axis crossing of a line fitted to the hyperpolarized portion of the current–voltage relationship mea- changes of the membrane capacitance (Cm; ref. 7). The speci- sured by a voltage ramp (Ϫ100 to ϩ60 mV within 20 ms) 20 ms ficity of Cm measurements for reporting exocytosis of neuro- transmitters has recently been confirmed in another ribbon-type after1sofdepolarization in separate sweeps (data not shown). presynapse, that of the goldfish retinal bipolar nerve terminal, by Setting the reversal potential used for software lock-in Cm Ϫ simultaneously recording transmitter release (8). In these neu- estimation to the measured value (values ranging from 45 to Ϫ rons, as well as in neuroendocrine cells, several kinetic compo- 65 mV) removed the rapid Cm transients observed when an nents of exocytosis have been observed and attributed to release inappropriate reversal potential was entered into the Cm calcu- Ϯ of functionally different pools of vesicles (9–12). We compare lation. The mean Cm of IHCs was 8.2 0.1 pF (random sample Ϯ the presynaptic properties of IHCs to the findings in other of 32 cells); the mean access resistances amounted to 9.9 1.0 ⍀ neurosecretory preparations and discuss them in the context of M (value after 200 s of recording; random sample of 18 auditory adaptation and recovery from adaptation. Materials and Methods This paper was submitted directly (Track II) to the PNAS office. Abbreviations: IHC, inner hair cell; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tet- Whole-Cell Recordings. IHCs from the apical coil of freshly dis- 2ϩ 2ϩ raacetate; [Ca ]i͞e, intracellular͞extracellular Ca concentration; Cm, membrane capac- sected organs of Corti from hearing mice (Naval Medical itance; RRP, readily releasable pool. Research Institute, postnatal days 14–40) were patch-clamped at †To whom reprint requests should be addressed. E-mail: [email protected]. their basolateral face at room temperature (20–25°C) or near ‡T.M. and D.B. contributed equally to this work. body temperature (35°C). Pipette solutions contained (in mM): The publication costs of this article were defrayed in part by page charge payment. This 145 Cs gluconate or Cs glutamate, 8 NaCl, 10 CsOH-Hepes, 1 article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. 2ϩ 2ϩ MgCl2, 2 MgATP, 0.3 GTP, and Ca chelators or Ca §1734 solely to indicate this fact. PNAS ͉ January 18, 2000 ͉ vol. 97 ͉ no. 1 ͉ 883–888 Downloaded by guest on September 25, 2021 Fig. 1. Exocytosis recorded by Cm measurements from single IHCs. (a) Simplified representation of an IHC, the measuring configuration, and an afferent IHC synapse (Inset) overlaid onto a Nomarski image of the explanted mouse organ of Corti (stereocilia of the row of IHCs are shown at the top of the image; cell bodies are covered by supporting cells). Previously suggested mechanisms of adaptation are indicated according to their localizations. Synaptic depression could be due 2ϩ 2ϩ to Ca current inactivation, vesicle depletion, or postsynaptic glutamate receptor desensitization. (b) IHCs kept at 35°C in 2 mM [Ca ]e were stimulated by a 50-ms depolarizing sinusoidal voltage (1 kHz; 40 mV peak to peak added to a dc potential of Ϫ50 mV; Upper). Four Cm traces recorded from three cells in the whole-cell configuration (0.1 mM EGTA added to the pipette solution) were averaged and smoothed by box averaging (n ϭ 3; Lower; horizontal lines represent Cm averages before and after stimulation). Cm estimation is not valid during the depolarization because of nonlinear conductance changes. (c) High time resolution plot of ⌬Cm and membrane currents measured in response to depolarizations (to Ϫ15 mV) of different durations in the perforated-patch configuration. ⌬Cm traces were smoothed by box averaging (n ϭ 3), and current traces were smoothed by binomial smoothing (n ϭ 5). Outward currents were ϩ (incompletely) inhibited by intracellular Cs and extracellular tetraethylammonium (35 mM). (Inset) Average of four ⌬Cm traces in response to 4-ms depolarizations (to Ϫ15 mV). (d) Representative membrane current response to a 50-ms depolarization to Ϫ15 mV in the presence of intracellular (13 mM) and extracellular (35 mM) tetraethylammonium. Very little decline (inactivation) of Ca2ϩ current was observed under these conditions. recordings) for standard whole-cell and to 17.7 Ϯ 1.8 M⍀ (value about 10 fF most likely reflects exocytosis of synaptic vesicles after 200 s of recording; random sample of 14 cells) for perfo- (about 280, as determined with a conversion factor of 37 aF per ⌬ ⌬ 2ϩ rated-patch recordings. Cm was estimated as the difference of vesicle; ref. 14). Fig. 1c shows Cm and Ca currents in response ⌬ the mean Cm over 400 ms after the end of the depolarization (the to step depolarizations of different lengths. Cm could be initial 30 ms were skipped) and the mean prepulse capacitance detected after very short stimuli and increased with longer (400 ms) for Figs. 3 a and b and 4 c and d. For Figs. 2c and 5, stimulation. The inward current showed some reduction with ⌬ ϩ Cm was estimated as the difference of the mean Cm over 40 ms time, in part reflecting activation of some unblocked K chan- after the depolarization (again skipping the initial 30 ms) and the nels and perhaps a very slow Ca2ϩ current inactivation for longer mean prepulse capacitance (40 ms before the depolarization).
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