Hörphysiologische Charakterisierung zweier Mausmodelle mit Schwerhörigkeit
Characterisation of hearing physiology in two mouse models with hearing loss
von Anna Ihler geb. Gehrt
Datum der mündl. Prüfung:2021-11-17
Erschienen:2021-11-11
Betreuer:Prof. Dr. Tobias Moser
Gutachter:Prof. Dr. Tobias Moser
Gutachter:Prof. Dr. Silvio O. Rizzoli
Dateien
Name:Dissertation Anna Ihler geb. Gehrt_ohneCV.pdf
Size:1.02Mb
Format:PDF
Description:Dissertation
Zusammenfassung
Englisch
In this work, two transgenic mouse models were characterized that showed disruption either of presynaptic Ca2+-influx (CaVβ2) in inner hair cells or of the cochlear K+-cycle (Cx26) by targeted mutagenesis. Approaches of systems physiology were established and applied to provide insight into the role of the Ca2+-channel subunit CaVβ2 into the coding of sound. Probably by positive regulation of the number of synaptic Ca2+-channels, CaVβ2 is an essential part of synaptic transmission at the synapse of the inner hair cell. Another role in outer hair cells was not investigated further. The assessment of early auditory evoked potentials showed profound hearing loss in CaVβ2-/--animals. Distortion products of otoacoustic emissions were missing almost completely. Extracellular microelectrode single unit recordings showed reduced activity that could be evoked only by high stimulation levels. Thereby, a reduction in the number of presynaptic Ca2+-channels at the inner hair cell synapse resulted in a considerably reduced rate of action potentials at the postsynapse. Spontaneous activity, dynamic range and thresholds showed only small variation. There was no degeneration of spiral ganglion neurons visible in immunohistochemistry. This seems to be caused by the number of CaV1.3 and the related amount of influx of Ca2+ into hair cells. Additionally, a minimal effect of pathological efferent nerve fibers is possible. An artifact in the form of a threshold shift by an acoustic trauma seems an unlikely explanation, since inner hair cells showed reduced exocytotic capabilities. The investigation into the effect of the point mutation S17F within GJB2, that causes the human KIT-syndrome, on cochlear function showed a reduction of the endocochlear potential as an important pathomechanism of Connexin26-dependent hearing loss. A reduced endocochlear potential correlated with increased thresholds for early auditory evoked potentials. The negative correlation of both findings suggests a causal relationship. Intracellular transport within the cochlea appears to be impaired. This most likely leads to a reduced influx of K+ in hair cells, a reduction of K+ in the endolymph and an increase of K+ in the Corti-lymph. Those changes could explain the dysfunction of inner and outer hair cells.
Keywords: hearing loss; transgenic animal model; inner hair cell; cochlea; electrophysiology