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Sharp Ca Nanodomains Beneath the Ribbon Promote Highly Synchronous Multivesicular Release at Hair Cell Synapses

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Sharp Ca Nanodomains Beneath the Ribbon Promote Highly Synchronous Multivesicular Release at Hair Cell Synapses The Journal of Neuroscience, November 16, 2011 • 31(46):16637–16650 • 16637 Cellular/Molecular Sharp Ca2ϩ Nanodomains beneath the Ribbon Promote Highly Synchronous Multivesicular Release at Hair Cell Synapses Cole W. Graydon,1,2* Soyoun Cho,3* Geng-Lin Li,3 Bechara Kachar,1 and Henrique von Gersdorff3 1National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, 2Brown–NIH Graduate Partnerships Program, Department of Neuroscience, Brown University, Providence, Rhode Island 02906, and 3The Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239 Hair cell ribbon synapses exhibit several distinguishing features. Structurally, a dense body, or ribbon, is anchored to the presynaptic membrane and tethers synaptic vesicles; functionally, neurotransmitter release is dominated by large EPSC events produced by seem- ingly synchronous multivesicular release. However, the specific role of the synaptic ribbon in promoting this form of release remains elusive. Using complete ultrastructural reconstructions and capacitance measurements of bullfrog amphibian papilla hair cells dialyzed 2ϩ with high concentrations of a slow Ca buffer (10 mM EGTA), we found that the number of synaptic vesicles at the base of the ribbon correlated closely to those vesicles that released most rapidly and efficiently, while the rest of the ribbon-tethered vesicles correlated to a 2ϩ second, slower pool of vesicles. Combined with the persistence of multivesicular release in extreme Ca buffering conditions (10 mM BAPTA),ourdataargueagainsttheCa 2ϩ-dependentcompoundfusionofribbon-tetheredvesiclesathaircellsynapses.Moreover,during hair cell depolarization, our results suggest that elevated Ca 2ϩ levels enhance vesicle pool replenishment rates. Finally, using Ca 2ϩ diffusion simulations, we propose that the ribbon and its vesicles define a small cytoplasmic volume where Ca 2ϩ buffer is saturated, 2ϩ despite 10 mM BAPTA conditions. This local buffer saturation permits fast and large Ca rises near release sites beneath the synaptic ribbonthatcantriggermultiquantalEPSCs.Weconcludethat,byrestrictingtheavailablepresynapticvolume,theribbonmaybecreating conditions for the synchronous release of a small cohort of docked vesicles. Introduction influenced by Ca 2ϩ and depends on a Ca 2ϩ-sensor protein At hair cell afferent synapses, a synaptic ribbon is affiliated with unique to hair cells called otoferlin (Roux et al., 2006; Johnson et the sites of Ca 2ϩ channel clustering and exocytosis (Zenisek et al., al., 2008; Pangrsic et al., 2010). 2004; Frank et al., 2010). The ribbon tethers a shell of synaptic Another hallmark of ribbon function is multivesicular release, vesicles, a small subset of which dock onto, or reside very close to, in which more than one vesicle fuses at a single synapse to pro- the presynaptic membrane. Remarkably, hair cell ribbon syn- duce EPSCs that are much larger than mEPSCs (Glowatzki and apses can sustain high release rates of several hundred vesicles per Fuchs, 2002; Grant et al., 2010). In frog hair cells, a transition second over prolonged periods (Parsons et al., 1994). This seem- from mEPSCs to predominantly large EPSCs occurs with a small ingly inexhaustible supply of vesicles is presumed to result from a difference in presynaptic membrane potential of only a few mil- vigorous replenishment of the ribbon-associated vesicles by the livolts (Li et al., 2009), suggesting that this transition occurs with multitude of vesicles that populate the surrounding cytoplasm. the incremental opening of a few Ca 2ϩ channels per synapse Mechanisms for signaling, transporting, and mobilizing these (Brandt et al., 2005; Jarsky et al., 2010). Two leading hypotheses vesicles remain unclear, although vesicle pool replenishment is have been proposed to explain multivesicular release. One in- volves the homotypic fusion of vesicles (so called, compound fusion) (Matthews and Sterling, 2008); the other, the coordinated Received April 13, 2011; revised Sept. 15, 2011; accepted Sept. 25, 2011. fusions of several docked vesicles at the plasma membrane Authorcontributions:C.W.G.,S.C.,G.-L.L.,B.K.,andH.v.G.designedresearch;C.W.G.,S.C.,andG.-L.L.performed research; C.W.G., S.C., G.-L.L., B.K., and H.v.G. analyzed data; C.W.G., S.C., G.-L.L., B.K., and H.v.G. wrote the paper. (Singer et al., 2004). However, both explanations are confounded This work was supported by NIDCD Grant DC04274 (H.v.G.), a Deafness Research Foundation Grant and a Tartar by the fact that multivesicular release remains robust even upon Fellowship (S.C.), a K99 Research Award from NIDCD (G.-L.L.), and the NIDCD Division of Intramural Research the introduction of strong presynaptic Ca 2ϩ buffering (Goutman (C.W.G., B.K.). We thank Will Grimes and Gary Matthews for discussions. *C.W.G. and S.C. contributed equally to this work. and Glowatzki, 2007), which is estimated to restrict the mean 2ϩ Correspondence should be addressed to either of the following: Bechara Kachar, National Institute on Deafness distance of free Ca diffusion to Ͻ10 nm from the pore of the 2ϩ andOtherCommunicationDisorders,NationalInstitutesofHealth,50SouthDrive,MSC8027,Bethesda,MD20892- Ca channel for 10 mM BAPTA (Bucurenciu et al., 2008; 8027, E-mail: [email protected]; or Henrique von Gersdorff, The Vollum Institute, Oregon Health & Science Parekh, 2008). In the context of these tight spatial constraints, the University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, E-mail: [email protected]. DOI:10.1523/JNEUROSCI.1866-11.2011 large size of some multivesicular EPSCs (composed of five or ϩ Copyright © 2011 the authors 0270-6474/11/3116637-14$15.00/0 more vesicles) is baffling, especially considering the low Ca 2 16638 • J. Neurosci., November 16, 2011 • 31(46):16637–16650 Graydon et al. • Vesicle Pool Sizes at Auditory Ribbon Synapses ⌬ ϭ Ϫ sensitivity of the release machinery of the hair cell (Beutner et al., capacitance, Cm Cm (response) Cm (baseline), was used as a proxy 2001). of total synaptic vesicle exocytosis from a single hair cell. An average of The complex relationship between vesicle populations and Cm (response) and Cm (baseline) was obtained by averaging Cm data points Ca 2ϩ influx into the crowded presynaptic space under a synaptic before and after the depolarizing pulse. Data analysis was performed with ribbon has yet to be fully characterized. Here, we combine elec- IGOR Pro software (Wavemetrics) and Prism (GraphPad Software). Resonant frequencies of hair cells. To measure the resonant frequency, trophysiology with a thorough ultrastructural analysis to deter- we injected step current into the hair cells and measured the resulting mine the size of morphologically and functionally defined vesicle 2ϩ membrane potential oscillations. These membrane potential oscillations pools at an adult hair cell synapse. We find that a slow Ca decayed exponentially in amplitude and reached a steady-state mem- buffer (10 mM EGTA) can decrease vesicle recruitment rates and brane potential (Vss). To calculate the resonant frequency ( fc), we fit the thus uncovers the size of two distinct vesicle pools. Furthermore, current-clamp data points using the following equation: V(t) ϭ ⅐ ␲ ⅐ ⅐ Ϫ ϩ ␾ ⅐ Ϫ Ϫ ␶ ϩ by incorporating our ultrastructural findings into Monte Carlo A sin(2 fc (t t0) ) exp[ (t t0)/ ] Vss, where A is the simulations of Ca 2ϩ influx at ribbon-type active zones, we sug- amplitude of voltage oscillation, ␾ is the phase, and ␶ is the single expo- nential decay time constant (Crawford and Fettiplace, 1981). gest that volume exclusion by the presence of the ribbon and its ϩ 2ϩ Noise analysis on Ca2 tail currents. Nonstationary noise analysis of associated vesicles can produce a sharp local Ca rise and ac- 2ϩ 2ϩ count for the observed characteristics of multivesicular release at Ca currents was used to estimate the number of Ca channels per hair cell and their single-channel current (Roberts et al., 1990). To obtain auditory hair cell synapses. ϩ a complete relationship between the mean and variance of the Ca 2 2ϩ currents for low- and high-amplitude Ca currents, we included 5 ␮M Materials and Methods 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3- Tissue and hair cell preparation. All procedures followed the Oregon pyridinecarboxylic acid, methyl ester (BayK 8644), in the bath solution to 2ϩ Health & Sciences University or National Institutes of Health (protocol maximize the open probability of the L-type Ca channels of the hair 2ϩ 1215-08) approved animal care protocols and guidelines. For physiology cell (Fox et al., 1987). To keep resting Ca levels very low, hair cells were 2ϩ studies, adult bullfrogs (Rana catesbeiana) of either sex were sedated by first held at Ϫ90 mV, and then stepped to Ϫ110 mV to relieve Ca ϩ placing them in an ice bath for ϳ20 min, and then double-pithed and channels from any Ca 2 or voltage-dependent inactivation. This was decapitated. Amphibian papillae were carefully dissected from the frog’s followed by a step depolarization to ϩ30 mV, opening all (or nearly all) ϩ ear. To expose hair cells and afferent fibers for patch clamping, amphib- of the Ca 2 channels. A membrane voltage step back to Ϫ90 mV pro- ian papilla were stretched out and split with fine microtools in a record- duced a large and sudden increase of driving force. As a result, a large ϩ ing chamber with oxygenated artificial perilymph (Keen and Hudspeth, Ca 2 tail current was elicited through the open channels, which de- ϩ 2006; Li et al., 2009). Artificial perilymph contained the following (in creased quickly as the Ca 2 channels reclosed (see Fig. 6B). For each hair mM): 95 NaCl, 2 KCl, 2 CaCl2, 1 MgCl2, 25 NaHCO3, 3 glucose, 1 crea- cell, we collected a total of 100 leak-subtracted current traces (elicited tine, 1 sodium pyruvate, pH adjusted to 7.3, and bubbled with 95% O2 every 100 ms), and the mean and variance of these currents were calcu- and 5% CO2.
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