Wichmann, Carolin

[["dc.bibliographiccitation.firstpage","7742"],["dc.bibliographiccitation.issue","37"],["dc.bibliographiccitation.journal","The Journal of Neuroscience"],["dc.bibliographiccitation.lastpage","7767"],["dc.bibliographiccitation.volume","41"],["dc.contributor.author","Butola, Tanvi"],["dc.contributor.author","Alvanos, Theocharis"],["dc.contributor.author","Hintze, Anika"],["dc.contributor.author","Koppensteiner, Peter"],["dc.contributor.author","Kleindienst, David"],["dc.contributor.author","Shigemoto, Ryuichi"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2022-02-22T14:54:23Z"],["dc.date.available","2022-02-22T14:54:23Z"],["dc.date.issued","2021"],["dc.description.abstract","Rab-interacting molecule (RIM)-binding protein 2 (BP2) is a multidomain protein of the presynaptic active zone (AZ). By binding to RIM, bassoon (Bsn), and voltage-gated Ca2+ channels (CaV), it is considered to be a central organizer of the topography of CaV and release sites of synaptic vesicles (SVs) at the AZ. Here, we used RIM-BP2 knock-out (KO) mice and their wild-type (WT) littermates of either sex to investigate the role of RIM-BP2 at the endbulb of Held synapse of auditory nerve fibers (ANFs) with bushy cells (BCs) of the cochlear nucleus, a fast relay of the auditory pathway with high release probability. Disruption of RIM-BP2 lowered release probability altering short-term plasticity and reduced evoked EPSCs. Analysis of SV pool dynamics during high-frequency train stimulation indicated a reduction of SVs with high release probability but an overall normal size of the readily releasable SV pool (RRP). The Ca2+-dependent fast component of SV replenishment after RRP depletion was slowed. Ultrastructural analysis by superresolution light and electron microscopy revealed an impaired topography of presynaptic CaV and a reduction of docked and membrane-proximal SVs at the AZ. We conclude that RIM-BP2 organizes the topography of CaV, and promotes SV tethering and docking. This way RIM-BP2 is critical for establishing a high initial release probability as required to reliably signal sound onset information that we found to be degraded in BCs of RIM-BP2-deficient mice in vivo SIGNIFICANCE STATEMENT Rab-interacting molecule (RIM)-binding proteins (BPs) are key organizers of the active zone (AZ). Using a multidisciplinary approach to the calyceal endbulb of Held synapse that transmits auditory information at rates of up to hundreds of Hertz with submillisecond precision we demonstrate a requirement for RIM-BP2 for normal auditory signaling. Endbulb synapses lacking RIM-BP2 show a reduced release probability despite normal whole-terminal Ca2+ influx and abundance of the key priming protein Munc13-1, a reduced rate of SV replenishment, as well as an altered topography of voltage-gated (CaV)2.1 Ca2+ channels, and fewer docked and membrane proximal synaptic vesicles (SVs). This hampers transmission of sound onset information likely affecting downstream neural computations such as of sound localization."],["dc.identifier.doi","10.1523/JNEUROSCI.0586-21.2021"],["dc.identifier.pmid","34353898"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/100192"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/382"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/147"],["dc.language.iso","en"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | A04: Aktivitätsabhängige morphologische Veränderungen am Endkolben von Held-Synapsen"],["dc.relation","SFB 1286 | B05: Quantitative molekulare Physiologie aktiver Zonen in Calyx-Synapsen"],["dc.relation.eissn","1529-2401"],["dc.relation.issn","0270-6474"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.relation.workinggroup","RG Wichmann (Molecular Architecture of Synapses)"],["dc.title","RIM-Binding Protein 2 Organizes Ca2+ Channel Topography and Regulates Release Probability and Vesicle Replenishment at a Fast Central Synapse"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","95"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cell and Tissue Research"],["dc.bibliographiccitation.lastpage","114"],["dc.bibliographiccitation.volume","361"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2017-09-07T11:43:44Z"],["dc.date.available","2017-09-07T11:43:44Z"],["dc.date.issued","2015"],["dc.description.abstract","In the mammalian cochlea, sound is encoded at synapses between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs). Each SGN receives input from a single IHC ribbon-type active zone (AZ) and yet SGNs indefatigably spike up to hundreds of Hz to encode acoustic stimuli with submillisecond precision. Accumulating evidence indicates a highly specialized molecular composition and structure of the presynapse, adapted to suit these high functional demands. However, we are only beginning to understand key features such as stimulus-secretion coupling, exocytosis mechanisms, exo-endocytosis coupling, modes of endocytosis and vesicle reformation, as well as replenishment of the readily releasable pool. Relating structure and function has become an important avenue in addressing these points and has been applied to normal and genetically manipulated hair cell synapses. Here, we review some of the exciting new insights gained from recent studies of the molecular anatomy and physiology of IHC ribbon synapses."],["dc.identifier.doi","10.1007/s00441-014-2102-7"],["dc.identifier.gro","3141877"],["dc.identifier.isi","000357115200009"],["dc.identifier.pmid","25874597"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11594"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2067"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Springer"],["dc.relation.eissn","1432-0878"],["dc.relation.issn","0302-766X"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Relating structure and function of inner hair cell ribbon synapses"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","jcs236737"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Journal of Cell Science"],["dc.bibliographiccitation.volume","133"],["dc.contributor.author","Kroll, Jana"],["dc.contributor.author","Özçete, Özge Demet"],["dc.contributor.author","Jung, Sangyong"],["dc.contributor.author","Maritzen, Tanja"],["dc.contributor.author","Milosevic, Ira"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2020-12-10T18:41:54Z"],["dc.date.available","2020-12-10T18:41:54Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1242/jcs.236737"],["dc.identifier.eissn","1477-9137"],["dc.identifier.issn","0021-9533"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77721"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","AP180 promotes release site clearance and clathrin-dependent vesicle reformation in mouse cochlear inner hair cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2686"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","EMBO Journal"],["dc.bibliographiccitation.lastpage","2702"],["dc.bibliographiccitation.volume","34"],["dc.contributor.author","Jung, SangYong"],["dc.contributor.author","Maritzen, Tanja"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Jing, Zhizi"],["dc.contributor.author","Neef, Andreas"],["dc.contributor.author","Revelo, Natalia H."],["dc.contributor.author","Al-Moyed, Hanan"],["dc.contributor.author","Meese, Sandra"],["dc.contributor.author","Wojcik, Sonja M."],["dc.contributor.author","Panou, Iliana"],["dc.contributor.author","Bulut, Haydar"],["dc.contributor.author","Schu, Peter"],["dc.contributor.author","Ficner, Ralf"],["dc.contributor.author","Reisinger, Ellen"],["dc.contributor.author","Rizzoli, Silvio"],["dc.contributor.author","Neef, Jakob"],["dc.contributor.author","Strenzke, Nicola"],["dc.contributor.author","Haucke, Volker"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2017-09-07T11:54:53Z"],["dc.date.available","2017-09-07T11:54:53Z"],["dc.date.issued","2015"],["dc.description.abstract","Active 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. Here, we report that the endocytic adaptor protein 2 (AP-2) is required for release site replenishment and hearing. We show that hair cell-specific disruption of AP-2 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. Sound-driven postsynaptic spiking was reduced in a use-dependent manner, and the altered interspike interval statistics suggested a slowed reloading of release sites. Sustained strong stimulation led to accumulation of endosome-like vacuoles, fewer clathrin-coated endocytic intermediates, andvesicle depletion of the membrane-distal synaptic ribbon in AP-2-deficient IHCs, indicating a further role of AP-2 in clathrin-dependent vesicle reformation on a timescale of many seconds. Finally, we show that AP-2 sorts its IHC-cargo otoferlin. We propose that binding of AP-2 to otoferlin facilitates replenishment of release sites, for example, via speeding AZ clearance of exocytosed material, in addition to a role of AP-2 in synaptic vesicle reformation."],["dc.identifier.doi","10.15252/embj.201591885"],["dc.identifier.gro","3141791"],["dc.identifier.isi","000364337100008"],["dc.identifier.pmid","26446278"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1112"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1460-2075"],["dc.relation.issn","0261-4189"],["dc.title","Disruption of adaptor protein 2μ (AP‐2μ) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","247"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","EMBO Journal"],["dc.bibliographiccitation.lastpage","264"],["dc.bibliographiccitation.volume","33"],["dc.contributor.author","Wong, Aaron B."],["dc.contributor.author","Rutherford, Mark A."],["dc.contributor.author","Gabrielaitis, Mantas"],["dc.contributor.author","Pangršič, Tina"],["dc.contributor.author","Göttfert, Fabian"],["dc.contributor.author","Frank, Thomas"],["dc.contributor.author","Michanski, Susann"],["dc.contributor.author","Hell, Stefan"],["dc.contributor.author","Wolf, Fred"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2017-09-07T11:46:33Z"],["dc.date.available","2017-09-07T11:46:33Z"],["dc.date.issued","2014"],["dc.description.abstract","Cochlear inner hair cells (IHCs) develop from pre-sensory pacemaker to sound transducer. Here, we report that this involves changes in structure and function of the ribbon synapses between IHCs and spiral ganglion neurons (SGNs) around hearing onset in mice. As synapses matured they changed from holding several small presynaptic active zones (AZs) and apposed postsynaptic densities (PSDs) to one large AZ/PSD complex per SGN bouton. After the onset of hearing (i) IHCs had fewer and larger ribbons; (ii) Ca(V)1.3 channels formed stripe-like clusters rather than the smaller and round clusters at immature AZs; (iii) extrasynaptic Ca(V)1.3-channels were selectively reduced, (iv) the intrinsic Ca2+ dependence of fast exocytosis probed by Ca2+ uncaging remained unchanged but (v) the apparent Ca2+ dependence of exocytosis linearized, when assessed by progressive dihydropyridine block of Ca2+ influx. Biophysical modeling of exocytosis at mature and immature AZ topographies suggests that Ca2+ influx through an individual channel dominates the [Ca2+] driving exocytosis at each mature release site. We conclude that IHC synapses undergo major developmental refinements, resulting in tighter spatial coupling between Ca2+ influx and exocytosis."],["dc.identifier.doi","10.1002/embj.201387110"],["dc.identifier.gro","3142187"],["dc.identifier.isi","000331394400008"],["dc.identifier.pmid","24442635"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/5499"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1460-2075"],["dc.relation.issn","0261-4189"],["dc.title","Developmental refinement of hair cell synapses tightens the coupling of Ca2+ influx to exocytosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Jean, Philippe"],["dc.contributor.author","Anttonen, Tommi"],["dc.contributor.author","Michanski, Susann"],["dc.contributor.author","de Diego, Antonio M. G."],["dc.contributor.author","Steyer, Anna M."],["dc.contributor.author","Neef, Andreas"],["dc.contributor.author","Oestreicher, David"],["dc.contributor.author","Kroll, Jana"],["dc.contributor.author","Nardis, Christos"],["dc.contributor.author","Pangršič, Tina"],["dc.contributor.author","Möbius, Wiebke"],["dc.contributor.author","Ashmore, Jonathan"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2021-04-14T08:25:48Z"],["dc.date.available","2021-04-14T08:25:48Z"],["dc.date.issued","2020"],["dc.description.abstract","Inner hair cells (IHCs) are the primary receptors for hearing. They are housed in the cochlea and convey sound information to the brain via synapses with the auditory nerve. IHCs have been thought to be electrically and metabolically independent from each other. We report that, upon developmental maturation, in mice 30% of the IHCs are electrochemically coupled in ‘mini-syncytia’. This coupling permits transfer of fluorescently-labeled metabolites and macromolecular tracers. The membrane capacitance, Ca2+-current, and resting current increase with the number of dye-coupled IHCs. Dual voltage-clamp experiments substantiate low resistance electrical coupling. Pharmacology and tracer permeability rule out coupling by gap junctions and purinoceptors. 3D electron microscopy indicates instead that IHCs are coupled by membrane fusion sites. Consequently, depolarization of one IHC triggers presynaptic Ca2+-influx at active zones in the entire mini-syncytium. Based on our findings and modeling, we propose that IHC-mini-syncytia enhance sensitivity and reliability of cochlear sound encoding."],["dc.identifier.doi","10.1038/s41467-020-17003-z"],["dc.identifier.pmid","32587250"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81736"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/383"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","2041-1723"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.relation.workinggroup","RG Möbius"],["dc.relation.workinggroup","RG Pangršič Vilfan (Experimental Otology)"],["dc.relation.workinggroup","RG Wichmann (Molecular Architecture of Synapses)"],["dc.rights","CC BY 4.0"],["dc.title","Macromolecular and electrical coupling between inner hair cells in the rodent cochlea"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","eLife"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Jean, Philippe"],["dc.contributor.author","Lopez de la Morena, David"],["dc.contributor.author","Michanski, Susann"],["dc.contributor.author","Jaime Tobón, Lina María"],["dc.contributor.author","Gültas, Mehmet"],["dc.contributor.author","Maxeiner, Stephan"],["dc.contributor.author","Strenzke, Nicola"],["dc.contributor.author","Chakrabarti, Rituparna"],["dc.contributor.author","Picher, Maria Magdalena"],["dc.contributor.author","Neef, Jakob"],["dc.contributor.author","Jung, SangYong"],["dc.contributor.author","Neef, Andreas"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Grabner, Chad"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2020-11-24T10:41:13Z"],["dc.date.available","2020-11-24T10:41:13Z"],["dc.date.issued","2018"],["dc.description.abstract","We studied the role of the synaptic ribbon for sound encoding at the synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in mice lacking RIBEYE (RBEKO/KO). Electron and immunofluorescence microscopy revealed a lack of synaptic ribbons and an assembly of several small active zones (AZs) at each synaptic contact. Spontaneous and sound-evoked firing rates of SGNs and their compound action potential were reduced, indicating impaired transmission at ribbonless IHC-SGN synapses. The temporal precision of sound encoding was impaired and the recovery of SGN-firing from adaptation indicated slowed synaptic vesicle (SV) replenishment. Activation of Ca2+-channels was shifted to more depolarized potentials and exocytosis was reduced for weak depolarizations. Presynaptic Ca2+-signals showed a broader spread, compatible with the altered Ca2+-channel clustering observed by super-resolution immunofluorescence microscopy. We postulate that RIBEYE disruption is partially compensated by multi-AZ organization. The remaining synaptic deficit indicates ribbon function in SV-replenishment and Ca2+-channel regulation."],["dc.identifier.doi","10.7554/eLife.29275"],["dc.identifier.eissn","2050-084X"],["dc.identifier.pmid","29328020"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/69157"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation.issn","2050-084X"],["dc.title","The synaptic ribbon is critical for sound encoding at high rates and with temporal precision"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.contributor.author","Chakrabarti, Rituparna"],["dc.contributor.author","Jaime Tobon, Lina Maria"],["dc.contributor.author","Slitin, Loujin"],["dc.contributor.author","Redondo-Canales, Magdalena"],["dc.contributor.author","Hoch, Gerhard"],["dc.contributor.author","Slashcheva, Marina"],["dc.contributor.author","Fritsch, Elisabeth"],["dc.contributor.author","Bodensiek, Kai"],["dc.contributor.author","Özçete, Özge Demet"],["dc.contributor.author","Gültas, Mehmet"],["dc.contributor.author","Michanski, Susann"],["dc.contributor.author","Opazo, Felipe"],["dc.contributor.author","Neef, Jakob"],["dc.contributor.author","Pangrsic, Tina"],["dc.contributor.author","Moser, Tobias"],["dc.contributor.author","Wichmann, Carolin"],["dc.date.accessioned","2022-08-24T05:56:10Z"],["dc.date.available","2022-08-24T05:56:10Z"],["dc.date.issued","2022"],["dc.identifier.doi","10.1101/2022.05.10.491334"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113153"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/483"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/164"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | Z04: Quantitative Visualisierung und Analyse synaptischer Proteine mit Hilfe von Nanobodies"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.relation.workinggroup","RG Pangršič Vilfan (Experimental Otology)"],["dc.relation.workinggroup","RG Wichmann (Molecular Architecture of Synapses)"],["dc.title","Optogenetics and electron tomography for structure-function analysis of cochlear ribbon synapses"],["dc.type","preprint"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2536"],["dc.bibliographiccitation.issue","23"],["dc.bibliographiccitation.journal","EMBO Journal"],["dc.bibliographiccitation.lastpage","2552"],["dc.bibliographiccitation.volume","35"],["dc.contributor.author","Vogl, Christian"],["dc.contributor.author","Panou, Iliana"],["dc.contributor.author","Yamanbaeva, Gulnara"],["dc.contributor.author","Wichmann, Carolin"],["dc.contributor.author","Mangosing, Sara J."],["dc.contributor.author","Vilardi, Fabio"],["dc.contributor.author","Indzhykulian, Artur A."],["dc.contributor.author","Pangršič, Tina"],["dc.contributor.author","Santarelli, Rosamaria"],["dc.contributor.author","Rodriguez‐Ballesteros, Montserrat"],["dc.contributor.author","Weber, Thomas"],["dc.contributor.author","Jung, Sangyong"],["dc.contributor.author","Cardenas, Elena"],["dc.contributor.author","Wu, Xudong"],["dc.contributor.author","Wojcik, Sonja M."],["dc.contributor.author","Kwan, Kelvin Y."],["dc.contributor.author","Castillo, Ignacio del"],["dc.contributor.author","Schwappach, Blanche"],["dc.contributor.author","Strenzke, Nicola"],["dc.contributor.author","Corey, David P"],["dc.contributor.author","Lin, Shuh‐Yow"],["dc.contributor.author","Moser, Tobias"],["dc.date.accessioned","2017-09-07T11:54:19Z"],["dc.date.available","2017-09-07T11:54:19Z"],["dc.date.issued","2016"],["dc.description.abstract","The transmembrane recognition complex (TRC40) pathway mediates the insertion of tail‐anchored (TA) proteins into membranes. Here, we demonstrate that otoferlin, a TA protein essential for hair cell exocytosis, is inserted into the endoplasmic reticulum (ER) via the TRC40 pathway. We mutated the TRC40 receptor tryptophan‐rich basic protein (Wrb) in hair cells of zebrafish and mice and studied the impact of defective TA protein insertion. Wrb disruption reduced otoferlin levels in hair cells and impaired hearing, which could be restored in zebrafish by transgenic Wrb rescue and otoferlin overexpression. Wrb‐deficient mouse inner hair cells (IHCs) displayed normal numbers of afferent synapses, Ca2+ channels, and membrane‐proximal vesicles, but contained fewer ribbon‐associated vesicles. Patch‐clamp of IHCs revealed impaired synaptic vesicle replenishment. In vivo recordings from postsynaptic spiral ganglion neurons showed a use‐dependent reduction in sound‐evoked spiking, corroborating the notion of impaired IHC vesicle replenishment. A human mutation affecting the transmembrane domain of otoferlin impaired its ER targeting and caused an auditory synaptopathy. We conclude that the TRC40 pathway is critical for hearing and propose that otoferlin is an essential substrate of this pathway in hair cells."],["dc.identifier.doi","10.15252/embj.201593565"],["dc.identifier.fs","626014"],["dc.identifier.gro","3145137"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2840"],["dc.language.iso","en"],["dc.notes.intern","Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","0261-4189"],["dc.title","Tryptophan‐rich basic protein (WRB) mediates insertion of the tail‐anchored protein otoferlin and is required for hair cell exocytosis and hearing"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","638"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Journal of Cell Science"],["dc.bibliographiccitation.lastpage","644"],["dc.bibliographiccitation.volume","128"],["dc.contributor.author","Vogl, Christian"],["dc.contributor.author","Cooper, Benjamin H."],["dc.contributor.author","Neef, Jakob"],["dc.contributor.author","Wojcik, Sonja M."],["dc.contributor.author","Reim, Kerstin"],["dc.contributor.author","Reisinger, Ellen"],["dc.contributor.author","Brose, Nils"],["dc.contributor.author","Rhee, Jeong-Seop"],["dc.contributor.author","Moser, Tobias"],["dc.contributor.author","Wichmann, Carolin"],["dc.date.accessioned","2017-09-07T11:44:35Z"],["dc.date.available","2017-09-07T11:44:35Z"],["dc.date.issued","2015"],["dc.description.abstract","Ribbon synapses of cochlear inner hair cells (IHCs) employ efficient vesicle replenishment to indefatigably encode sound. In neurons, neuroendocrine and immune cells, vesicle replenishment depends on proteins of the mammalian uncoordinated 13 (Munc13, also known as Unc13) and Ca2+-dependent activator proteins for secretion (CAPS) families, which prime vesicles for exocytosis. Here, we tested whether Munc13 and CAPS proteins also regulate exocytosis in mouse IHCs by combining immunohistochemistry with auditory systems physiology and IHC patch-clamp recordings of exocytosis in mice lacking Munc13 and CAPS isoforms. Surprisingly, we did not detect Munc13 or CAPS proteins at IHC presynaptic active zones and found normal IHC exocytosis as well as auditory brainstem responses (ABRs) in Munc13 and CAPS deletion mutants. Instead, we show that otoferlin, a C-2-domain protein that is crucial for vesicular fusion and replenishment in IHCs, clusters at the plasma membrane of the presynaptic active zone. Electron tomography of otoferlin-deficient IHC synapses revealed a reduction of short tethers holding vesicles at the active zone, which might be a structural correlate of impaired vesicle priming in otoferlin-deficient IHCs. We conclude that IHCs use an unconventional priming machinery that involves otoferlin."],["dc.identifier.doi","10.1242/jcs.162099"],["dc.identifier.gro","3141957"],["dc.identifier.isi","000349786500004"],["dc.identifier.pmid","25609709"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2957"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1477-9137"],["dc.relation.issn","0021-9533"],["dc.title","Unconventional molecular regulation of synaptic vesicle replenishment in cochlear inner hair cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]