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Control of Exocytosis by Synaptotagmins and Otoferlin in Auditory Hair Cells

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Control of Exocytosis by Synaptotagmins and Otoferlin in Auditory Hair Cells Control of exocytosis by synaptotagmins and otoferlin in auditory hair cells. Maryline Beurg, Nicolas Michalski, Saaid Safieddine, Yohan Bouleau, Ralf Schneggenburger, Edwin R Chapman, Christine Petit, Didier Dulon To cite this version: Maryline Beurg, Nicolas Michalski, Saaid Safieddine, Yohan Bouleau, Ralf Schneggenburger, et al.. Control of exocytosis by synaptotagmins and otoferlin in auditory hair cells.. Journal of Neuroscience, Society for Neuroscience, 2010, 30 (40), pp.13281-90. 10.1523/JNEUROSCI.2528-10.2010. pasteur- 01472847 HAL Id: pasteur-01472847 https://hal-pasteur.archives-ouvertes.fr/pasteur-01472847 Submitted on 30 Apr 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. The Journal of Neuroscience, October 6, 2010 • 30(40):13281–13290 • 13281 Cellular/Molecular Control of Exocytosis by Synaptotagmins and Otoferlin in Auditory Hair Cells Maryline Beurg,1 Nicolas Michalski,2 Saaid Safieddine,3 Yohan Bouleau,1 Ralf Schneggenburger,2 Edwin R. Chapman,4 Christine Petit,3,5 and Didier Dulon1 1Equipe Neurophysiologie de la Synapse Auditive, Institut National de la Sante´ et de la Recherche Me´dicale (Inserm), Unite´ Mixte de Re´cherche Scientifique (UMRS) 587, Universite´ Victor Segalen and Institut des Neurosciences de Bordeaux, Centre Hospitalier Universitaire Pellegrin, 33076 Bordeaux, France, 2Laboratory of Synaptic Mechanisms, Brain-Mind Institute, Ecole Polytechnique Fe´de´rale de Lausanne, 1015 Lausanne, Switzerland, 3Unite´deGe´ne´tique et Physiologie de l’Audition, Inserm UMRS 587, Institut Pasteur et Universite´ Pierre et Marie Curie, 75724 Paris, France, 4Howard Hughes Medical Institute and Department of Physiology, University of Wisconsin, Madison, Wisconsin 53706, and 5Colle`ge de France, 75005 Paris, France In pre-hearing mice, vesicle exocytosis at cochlear inner hair cell (IHC) ribbon synapses is triggered by spontaneous Ca 2ϩ spikes. At the onset of hearing, IHC exocytosis is then exclusively driven by graded potentials, and is characterized by higher Ca 2ϩ efficiency and improvedsynchronizationofvesicularrelease.Themolecularplayersinvolvedinthistransitionarestillunknown.Hereweaddressedthe involvement of synaptotagmins and otoferlin as putative Ca 2ϩ sensors in IHC exocytosis during postnatal maturation of the cochlea. Using cell capacitance measurements, we showed that Ca 2ϩ-evoked exocytosis in mouse IHCs switches from an otoferlin-independent to an otoferlin-dependent mechanism at postnatal day 4. During this early exocytotic period, several synaptotagmins (Syts), including Syt1, Syt2 and Syt7, were detected in IHCs. The exocytotic response as well as the release of the readily releasable vesicle pool (RRP) was, however, unchanged in newborn mutant mice lacking Syt1, Syt2 or Syt7 (Syt1 Ϫ/ Ϫ, Syt2 Ϫ/ Ϫ and Syt7 Ϫ/ Ϫ mice). We only found a defect in RRP recovery in Syt1 Ϫ/ Ϫ mice which was apparent as a strongly reduced response to repetitive stimulations. In post-hearing Syt2 Ϫ/ Ϫ and Syt7 Ϫ/ Ϫ mutant mice, IHC synaptic exocytosis was unaffected. The transient expression of Syt1 and Syt2, which were no longer detected in IHCs after the onset of hearing, indicates that these two most common Ca 2ϩ-sensors in CNS synapses are not involved in mature IHCs. We suggest that otoferlin underlies highly efficient Ca 2ϩ-dependent membrane-membrane fusion, a process likely essen- tial to increase the probability and synchrony of vesicle fusion events at the mature IHC ribbon synapse. Introduction al., 2003), and the efficiency of brief Ca 2ϩ currents in evoking Before the onset of hearing, cochlear inner hair cells (IHCs) ex- release increases with cell maturation (Beutner and Moser, 2001; hibit spontaneous Ca 2ϩ spiking activity that triggers synaptic Johnson et al., 2005). Synchronization of the multivesicular re- exocytosis (Kros et al., 1998; Beutner et al., 2001; Marcotti et al., lease process (Glowatzki and Fuchs, 2002) also improves with 2003; Tritsch and Bergles, 2010) and postsynaptic trains of action IHC maturation (Grant et al., 2010), which suggests that con- potentials (APs) in cochlear ganglion neurons (Lippe, 1994; comitant, as yet poorly understood changes take place in the IHC Jones et al., 2007; Tritsch et al., 2007). In mature IHCs, exocytosis synaptic machinery. is then driven by sound-evoked fast graded receptor potentials. In Like in most neurosecretory cells, synaptic exocytosis in both immature and mature IHCs, neurotransmitter release is IHCs is thought to involve interactions of SNARE (soluble 2ϩ 2ϩ triggered by Ca influx flowing through L-type Ca channels N-ethylmaleimide-sensitive-factor attachment protein receptor) (Moser and Beutner, 2000; Glowatzki and Fuchs, 2002; Brandt et complex proteins attached to synaptic vesicles (synaptobrevin) with the target plasma membrane (SNAP-25 and syntaxin 1) Received May 18, 2010; revised July 22, 2010; accepted July 30, 2010. (Safieddine and Wenthold, 1999). Synaptotagmins (Syts), a large This work was supported by grants from the European Commission FP6 Integrated Project EuroHear (LSHG-CT- family of transmembrane proteins containing tandem Ca 2ϩ- 2004-512063), the French National Research Agency (ANR-07-Neuroscience), Louis-Jeantet for Medecine Founda- binding C2-domains, confer Ca 2ϩ sensitivity to SNARE- tion(C.P.),theFondationVoir&Entendre,andNationalInstitutesofHealthGrantR01-MH06186(E.R.C.).E.R.C.isan InvestigatoroftheHowardHughesMedicalInstitute.N.M.wassupportedbytheEMBO(EuropeanMolecularBiology dependent vesicle fusion in the CNS (Chapman, 2008), but their Organization) Long Term Fellowship (ALTF 724-2008). We thank Norma Andrews at the University of Maryland for implication in IHC synaptic exocytosis is still unclear. Indeed, the providinguswiththeSyt7-nullmice,andRobertoAdachiandThomasC.Su¨dhofforprovidinguswithSyt2-nullmice. transcripts encoding Syt1 and Syt2, the major Ca 2ϩ sensors for We also thank Robert Fettiplace for his scientific support and advice, Huisheng Liu for his help on Syt1 and Syt7 projects, Jean-Pierre Hardelin for critical reading of the manuscript, and Lance Rodenkirch and Mireille Montcou- fast synchronized transmitter release in central neurons (Geppert quiol for their help with confocal microscopy. et al., 1994; Sun et al., 2007), have not been detected in mature Correspondence should be addressed to any of the following: Maryline Bordeaux, E-mail: maryline.beurg@ IHCs (Safieddine and Wenthold, 1999). Therefore, otoferlin, a inserm.fr, Christine Petit, E-mail: [email protected], or Didier Dulon, E-mail: [email protected] at the above six C2-domain transmembrane protein (Yasunaga et al., 1999), addresses. 2ϩ 2ϩ DOI:10.1523/JNEUROSCI.2528-10.2010 has been proposed as a major Ca sensor required for Ca - Copyright © 2010 the authors 0270-6474/10/3013281-10$15.00/0 evoked exocytosis in IHCs (Roux et al., 2006). 13282 • J. Neurosci., October 6, 2010 • 30(40):13281–13290 Beurg et al. • Calcium Sensors and Cochlear Hair Cells The synaptic active zone of IHCs has been proposed to be For action potential and afferent fiber recordings, the internal solution 2ϩ organized in independent Ca nanodomains, where the activity contained the following (in mM): 140 KCl, 3.5 MgCl2, 0.1 CaCl2, 5 EGTA, of one or few Ca 2ϩ channels is sufficient to activate release of a HEPES 5, pH 7.2. nearby vesicle (Brandt et al., 2005), allowing the synapse to func- Capacitance measurement. Changes in cell membrane capacitance (⌬C ) were used to monitor fusion of synaptic vesicles during exocyto- tion in a linear regime (Johnson et al., 2005; Keen and Hudspeth, m sis. C was measured according to the Lindau-Neher technique (Lindau 2006; Goutman and Glowatzki, 2007). Recently, Syt4, which does m and Neher, 1988), using the tracking circuitry of the Optopatch (exper- not bind Ca 2ϩ and is not established as a Ca 2ϩ sensor (von Poser 2ϩ iments on otoferlin-null mice) or implemented in the JClamp (Scisoft, et al., 1997), has been shown to be required for the linear Ca New Haven, CT) (Syt1-null or Syt7-null mice recordings), or the Patch- dependence of exocytosis (Johnson et al., 2010). Notably, this master softwares (Syt2-null mice). A 20 mV amplitude sine wave from a latter study also reported the expression of Syt1 and Syt2 in im- holding potential of Ϫ80 mV was used; for recording of Syt2-null mice, mature and mature IHCs, respectively, but the functional impli- the sine wave had an amplitude of 30 mV from a holding potential of Ϫ90 mV. The resulting maximal depolarizations to ϳϪ60 mV were suffi- cation of these findings has not yet been investigated. To clarify ϩ 2ϩ 2 the respective roles of these putative Ca sensors at the IHC ciently small to avoid activation of Ca current (ICa). The command ribbon synapse along the course of cochlear maturation, we stud- sine wave (781.3–1600 Hz) was blanked during the duration of the volt- ied their expression and analyzed Ca 2ϩ-dependent exocytosis in age step and resumed immediately upon repolarization to capture the Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ capacitance before and after the pulse. ⌬C was estimated as the mean IHCs
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