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Molecular physiology of synaptic sound encoding at the first auditory synapse

dc.contributor.advisorMoser, Tobias Prof. Dr.
dc.contributor.authorKrinner, Stefanie
dc.date.accessioned2018-03-20T10:21:57Z
dc.date.available2018-03-20T10:21:57Z
dc.date.issued2018-03-20
dc.identifier.urihttp://hdl.handle.net/11858/00-1735-0000-002E-E396-A
dc.identifier.urihttp://dx.doi.org/10.53846/goediss-6793
dc.language.isoengde
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc570de
dc.titleMolecular physiology of synaptic sound encoding at the first auditory synapsede
dc.typedoctoralThesisde
dc.contributor.refereeNeher, Erwin Prof. Dr.
dc.date.examination2017-11-22
dc.description.abstractengTo achieve accurate encoding of sounds, inner hair cell (IHC) ribbon-type synapses are highly specialized to release synaptic vesicles (SVs) with high rates and temporal precision. A sophisticated, by far not yet fully disentangled unconventional molecular machinery at the synapse active zone (AZ) realizes this impressive performance. It regulates the number of synaptic CaV1.3 Ca2+-channels, their tight coupling to SVs, and fast re-supply of SVs for sustained rates of exocytosis. Sound-evoked glutamate release from an IHC synapse is sensed by the postsynaptic spiral ganglion neurons (SGNs). Each SGN is innervated by only one ribbon-type synapse. Even though one might expect similar response characteristics from SGNs innervating the same IHC, this is surprisingly not the case. Postsynaptic spike responses of SGNs differ remarkably, which is likely used as a presynaptic mechanism to encode sounds of varying intensity. Recently, a positive correlation between different SGN response types and presynaptic synapse properties has been found. However, a functional link between heterogeneous presynaptic properties and postsynaptic SGN spike response diversity remains to be demonstrated. To draw a clearer picture of the synaptic transmission mechanism in IHCs, it is key to characterize the molecular components. Furthermore, it is critical to understand the coding strategies of sensory IHCs that specialize and fine-tune the synapses to mediate sound coding. In this work, I addressed these questions in two different approaches. (1) First, the molecular physiology of synaptic transmission at the IHC ribbon synapse was investigated by examining the role of RIM-binding protein 2 (RIM-BP2), a multidomain cytomatrix protein acting as molecular hub between Ca2+-channels and vesicular release sites. A multidisciplinary approach including confocal and STED immunofluorescence microscopy, electron microscopy, patch-clamp, and confocal Ca2+-imaging, as well as auditory systems physiology was utilized to explore the morphological and physiological effects of genetic RIM-BP2 disruption in constitutive RIM-BP2 knockout mice. I found evidence that RIM-BP2 positively regulates the number of synaptic CaV1.3 Ca2+-channels and thereby facilitates SV release and enhances fast SV recruitment after RRP depletion. Furthermore, recordings of auditory brainstem responses (ABRs) and of single auditory nerve fibers (ANFs) showed a mild deficit of sound encoding. (2) Second, an experimental setup for voltage imaging in SGNs was established, to simultaneously monitor multiple SGN responses innervating the same IHC and thereby create a system to understand the synaptic coding strategies of IHCs. The genetically encoded voltage indicators (GEVIs) QuasAr2 and 3 were specifically targeted to SGNs, however only QuasAr3 elicited fluorescence responses in SGN boutons adjacent to an IHC. Thus, henceforth QuasAr3 might be a suitable tool to probe the presynaptic mechanism of postsynaptic response diversity.de
dc.contributor.coRefereeHell, Stefan Prof. Dr.
dc.contributor.thirdRefereeBrose, Nils Prof. Dr.
dc.contributor.thirdRefereeDresbach, Thomas Prof. Dr.
dc.contributor.thirdRefereeSchmidt, Manuela Dr.
dc.subject.engRIM-BPde
dc.subject.engCalcium imagingde
dc.subject.engPatch-clampde
dc.subject.engSTED microscopyde
dc.subject.engVoltage imagingde
dc.subject.engRibbon synapsede
dc.subject.engCochleade
dc.identifier.urnurn:nbn:de:gbv:7-11858/00-1735-0000-002E-E396-A-3
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de
dc.identifier.ppn1016200137


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