Der Einfluss einer chronischen Lärmexposition auf die Degeneration des Corti-Organs von tauben Otoferlin-Knockout-Mäusen.
The influence of a chronic noise exposure on the degeneration of the organ of Corti of deaf otoferlin knockout mice.
by Albert Justin Franke
Date of Examination:2025-12-09
Date of issue:2025-12-02
Advisor:Prof. Dr. Nicola Strenzke
Referee:Prof. Dr. Silvio Rizzoli
Referee:Prof. Dr. Ralf Dressel
Persistent Address:
http://dx.doi.org/10.53846/goediss-11658
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Abstract
English
This study investigated the age-related and noise-associated degeneration of the organ of Corti in otoferlin knockout mice. This knockout causes a complete loss of otoferlin expression in the organ of Corti in mice and thus represents a model for researching mutations in the DFNB9 locus. The phenotype of DFNB9 is often characterized by prelingual, non-syndromic, autosomal recessive hearing loss. The cause is a synaptic disorder of the inner hair cells of the inner ear. Since the sound-amplifying outer hair cells are primarily intact, the disease may remain undetected during functional testing of the outer hair cells as part of newborn hearing screening. In addition to being treated with a power hearing aid or a cochlear implant, genetic repair of the gene locus for the expression of otoferlin by insertion of adeno-associated viruses is currently being tested. To obtain a better understanding of age-related degeneration and noise susceptibility of the inner ear in DFNB9 patients, we not only examined otoferlin knockout mice during aging, but also placed these mice in a self-configured noise setup with chronic sound exposure (40 hours/week) for three months at an intensity of 83 ± 1.5 dB. We hypothesized that deafness could trigger increased susceptibility to noise trauma due to the failure of the body's own protective reflexes, such as the middle ear reflex or the middle olive complex reflex. In addition to in vivo hearing tests to examine hearing function, we used immunofluorescence staining to quantify cell damage. Analysis of early auditory evoked potentials showed that already the non-exposed otoferlin knockout mice were unable to produce signals exceeding the summation potential. We thus confirmed the deafness of these animals. We used the comparison of auditory brainstem responses in exposed and unexposed wild-type animals to assess the severity of noise exposure with regard to the hearing damage caused. The exposed wild-type animals had significantly increased hearing thresholds in many frequency regions and the amplitude of the summation potential and the first wave in the auditory brainstem responses also decreased as a result of exposure. We could thus demonstrate the significant influence of chronic noise exposure on the degeneration of the organ of Corti in wild-type animals. By analyzing cell counts, we were able to detect a more pronounced age-related degeneration of the hair cells required for cochlear amplification, transduction, and transmission in otoferlin knockout mice. At 24 weeks, the number of inner hair cells across the entire length of the basilar membrane was already considerably reduced compared to 8-week-old animals, showing a large difference to wild-type animals, which had much more stable cell counts even at 34 weeks. In addition to the number of inner hair cells being reduced, the average length of these cells was also reduced. This difference was particularly prominent in regions where many hair cells had been lost. By examining the afferent synapses, we were able to show that the number of afferent synapses in otoferlin knockout mice was reduced by between 44 and 65% in the regions examined compared to wild-type animals. Using Imaris-supported analysis of the afferent synapses, we were able to demonstrate an enlargement of the presynapses and postsynapses in older otoferlin knockout mice, as already described in the literature for Vglut3-/- mice. The outer hair cells were also reduced in otoferlin knockout mice as a result of age-related accelerated degeneration, without any age-related degeneration of the efferent synapses. Noise trauma caused more severe hair cell loss in the sensory epithelium of otoferlin knockout mice than in wild-type animals. Analysis of the inner hair cells showed that apical hair cell density in particular was reduced. For the first time, we were able to demonstrate that the outer hair cells in otoferlin knockout mice degenerate even more severely than the inner hair cells as a result of chronic exposure to noise. We concluded that the decrease in otoacoustic emissions frequently observed in DFNB9 patients during treatment with a power hearing aid may be attributed to the pronounced degeneration of the outer hair cells during acoustic stimulation. Surprisingly, the number of afferent synapses in otoferlin knockout mice was very resilient to acoustic overstimulation. In contrast to wild-type animals, we did not observe any tendency toward afferent synapse loss in otoferlin knockout mice. In addition, sound exposure reduced the volume of postsynapses in otoferlin knockout mice. This is interesting since there is none or only minimal exocytosis, suggesting that the size of postsynapses must be regulated independently of glutamate. Furthermore, we observed a larger decrease in efferent synapses as a result of noise exposure in otoferlin knockout mice. In combination with the already increased age-related degeneration of the sensory epithelium, our data suggests that initial treatment with power hearing aids in DFNB9 patients should be critically questioned and long-term chronic sound exposure should be prevented with particular care. In addition, genetic treatment should be carried out as early as possible so that previous degeneration of the sensory epithelium does not severely limit hearing performance.
Keywords: DFNB9; otoferlin knockout mouse model; chronic noise exposure; hearing loss; organ of Corti
Schlagwörter: DFNB9; Otoferlin-Knockoutmauslinie; chronische Beschallung; Hörverlust; Corti-Organ
