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dc.contributor.advisor Moser, Tobias Prof. Dr.
dc.contributor.author Picher, Maria Magdalena
dc.date.accessioned 2016-11-29T09:58:03Z
dc.date.available 2016-11-29T09:58:03Z
dc.date.issued 2016-11-29
dc.identifier.uri http://hdl.handle.net/11858/00-1735-0000-002B-7CC1-F
dc.language.iso eng de
dc.relation.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc 570 de
dc.title The role of Calcium Binding Protein 2 in synaptic sound encoding and hearing de
dc.type doctoralThesis de
dc.contributor.referee Wolf, Fred Prof. Dr.
dc.date.examination 2015-12-02
dc.description.abstracteng Hearing is a unique sensory feature providing the individual with acoustic information about the surrounding environment. Humans rely on hearing to localize potential dangers and it is essential for communication and social interaction. Hearing impairment is the most common sensory deficit and affects approximately 360 million people world-wide according to the World Health Organization. Therefore, it is of great importance to understand the underlying mechanisms that enable hearing. At inner hair cell ribbon synapses, which are the first relay station of the auditory pathway, CaV1.3 calcium channels are presynaptic key elements modulating calcium-influx exocytosis coupling. In order to indefatigably respond to incoming sound waves, these CaV1.3 channels exhibit weak inactivation kinetics, but the underlying mechanisms are not understood. In the course of this study, a mutation in the gene encoding for calcium binding protein 2 (CaBP2) was shown to cause recessive, non-syndromic hearing impairment DFNB93. CaBPs are EF-hand calcium binding proteins, with high structural similarity to calmodulin and were implicated in regulating voltage-gated calcium channels, by preventing calmodulin-induced calcium-dependent inactivation. Therefore, we reasoned that CaBP2 might be one key regulator of CaV1.3 channels in inner hair cells. To study the role of CaBP2 in the auditory system and the underlying disease mechanism of DFNB93, a newly generated mouse model for DFNB93 was analyzed. Here, various approaches including in vitro patch clamp recordings of both, transiently transfected HEK293 cells and acutely dissected inner hair cells, immunohistochemistry, in vivo systems physiology and extracellular recordings of auditory nerve fibers were combined to elucidate the function of CaBP2. Using an improved heterologous expression system, CaBP2 was shown to shift the voltage-sensitivity of CaV1.3 channels and inhibit calcium-dependent inactivation, which indicate two mutually non-exclusive disease mechanisms for DFNB93: (i) a shifted calcium channel activation out of the physiological receptor potential range of inner hair cells and/or (ii) enhanced calcium channel inactivation resulting in a reduced number of available channels for mediating glutamate release. Moreover, CaBP2 deficient mice displayed an auditory synaptopathy characterized by impaired cochlear sound encoding, while active cochlear amplification remained intact. In vitro patch clamp recordings of inner hair cells finally confined enhanced CaV1.3 channel inactivation as a candidate mechanism for DFNB93. By using in vivo recordings of auditory nerve fibers, this calcium channel dysfunction was shown to result in reduced spike firing rates of auditory nerve fibers coinciding with impaired temporal precision. To evaluate the feasibility of a gene therapeutic approach to affected patients in future, viral mediated CaBP2 transfer into inner hair cells was established. A first set of experiments showed that CaBP2 overexpression by adeno associated virus 2/1 does not affect hearing in wild-type mice; however, the first attempt of transducing inner hair cells of CaBP2 deficient mice failed to restore hearing, thereby suggesting that this method requires further optimization. de
dc.contributor.coReferee Dresbach, Thomas Prof. Dr.
dc.subject.eng calcium binding protein de
dc.subject.eng calcium channel de
dc.subject.eng calcium-dependent inactivation de
dc.subject.eng calcium buffer de
dc.subject.eng inner hair cell de
dc.subject.eng ribbon synapse de
dc.subject.eng deafness de
dc.subject.eng hearing impairment de
dc.identifier.urn urn:nbn:de:gbv:7-11858/00-1735-0000-002B-7CC1-F-0
dc.affiliation.institute Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) de
dc.subject.gokfull Biologie (PPN619462639) de
dc.identifier.ppn 873444043

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