Pangršič Vilfan, Tina

[["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","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Oestreicher, David"],["dc.contributor.author","Picher, Maria Magdalena"],["dc.contributor.author","Rankovic, Vladan"],["dc.contributor.author","Moser, Tobias"],["dc.contributor.author","Pangrsic, Tina"],["dc.date.accessioned","2021-10-01T09:58:18Z"],["dc.date.available","2021-10-01T09:58:18Z"],["dc.date.issued","2021"],["dc.description.abstract","Clinical management of auditory synaptopathies like other genetic hearing disorders is currently limited to the use of hearing aids or cochlear implants. However, future gene therapy promises restoration of hearing in selected forms of monogenic hearing impairment, in which cochlear morphology is preserved over a time window that enables intervention. This includes non-syndromic autosomal recessive hearing impairment DFNB93, caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels Ca V 1.3. Based on disease modeling in Cabp2 –/– mice, DFNB93 hearing impairment has been ascribed to enhanced steady-state inactivation of IHC Ca V 1.3 channels, effectively limiting their availability to trigger synaptic transmission. This, however, does not seem to interfere with cochlear development and does not cause early degeneration of hair cells or their synapses. Here, we studied the potential of a gene therapeutic approach for the treatment of DFNB93. We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2 –/– mice and assessed the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC Ca V 1.3 function resulting in improved hearing of Cabp2 –/– mice. These preclinical results prove the feasibility of DFNB93 gene therapy."],["dc.description.abstract","Clinical management of auditory synaptopathies like other genetic hearing disorders is currently limited to the use of hearing aids or cochlear implants. However, future gene therapy promises restoration of hearing in selected forms of monogenic hearing impairment, in which cochlear morphology is preserved over a time window that enables intervention. This includes non-syndromic autosomal recessive hearing impairment DFNB93, caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels Ca V 1.3. Based on disease modeling in Cabp2 –/– mice, DFNB93 hearing impairment has been ascribed to enhanced steady-state inactivation of IHC Ca V 1.3 channels, effectively limiting their availability to trigger synaptic transmission. This, however, does not seem to interfere with cochlear development and does not cause early degeneration of hair cells or their synapses. Here, we studied the potential of a gene therapeutic approach for the treatment of DFNB93. We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2 –/– mice and assessed the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC Ca V 1.3 function resulting in improved hearing of Cabp2 –/– mice. These preclinical results prove the feasibility of DFNB93 gene therapy."],["dc.identifier.doi","10.3389/fnmol.2021.689415"],["dc.identifier.pmid","34489639"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/90035"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/418"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.publisher","Frontiers Media S.A."],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1662-5099"],["dc.relation.workinggroup","RG Moser (Molecular Anatomy, Physiology and Pathology of Sound Encoding)"],["dc.relation.workinggroup","RG Pangršič Vilfan (Experimental Otology)"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]