Auditory nerve function in mouse models of ATP11A and CABP1-CABP2 related hearing loss

by Shashank Chepurwar
Doctoral thesis
Date of Examination:2024-10-02
Date of issue:2025-02-10
Advisor:Dr. Nicola Strenzke
Referee:Dr. Martin Gopfert
Referee:Dr. Andreas Neef
Referee:Dr. Michael Sereda
Referee:Dr. Brett Carter
Referee:Dr. Thomas Frank
Persistent Address: http://dx.doi.org/10.53846/goediss-10945

 

 

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Abstract

English

Hearing loss can be caused by varied factors affecting diverse structures of the auditory system such as the middle ear, the stria vascularis, the outer hair cells (OHC), inner hair cells (IHC), the spiral ganglion neurons (SGN), and the central auditory system. Auditory synaptopathy/neuropathy is a hearing disorder caused by deficits of the IHC ribbon synapses or the SGNs. Clinically, it is characterized by absent or severely abnormal auditory brainstem responses (ABRs) and conserved function of the OHCs determined by preserved Distortion Product Otoacoustic Emissions (DPOAEs). Here, I use genetically modified mouse models to study the mechanisms of two independent genetic causes of auditory neuropathy, autosomal dominant auditory neuropathy type II (AUNA2) caused by mutations in ATP11A and autosomal recessive auditory synaptopathy DFNB93 caused by mutations in CABP2. Like AUNA2 patients, conditional Atp11a knockout mice showed an age-dependent reduction in ABR amplitudes. However, the single unit responses of their SGNs were quite normal. Interestingly, we observed a reduction in peak firing rates which together with a reduction in the number of IHC-SGN synapses may explain the ABR phenotype. In contrast, the very strong ABR amplitude reduction in Cabp1-Cabp2 double knockout mice was found to correlate with a drastic reduction of SGN action potential firing. Enhanced synaptic CaV1.3 Ca2+ channel inactivation in the IHCs led to enhanced SGN firing rate adaptation. By increasing the duration of the silent interstimulus interval, I observed that the sound onset spike rates of mutants improved with an increased jitter and latency of the first-spike. These observations suggest the synergistic action of Cabp1-Cabp2 is crucial for maintaining the calcium channels in a non-inactivated state and for sustained synaptic transmission at IHC ribbon synapses. The comparison between the two mutants underlines that very diverse processes can cause auditory neuropathy and suggest that the clinical interventions to restore hearing need to thus focus on specific functional units of the auditory system. This study implicates the electrophysiological investigations in the auditory nerve as a crucial and essential experiment to confirm and assess the severity of an auditory deficit, to functionally characterize the phenotype of auditory neurotransmission and effectively elucidate the disease mechanism of etiologically diverse hearing disorders.
Keywords: auditory neuroscience; deafness; AUNA2; ATP11a; CABP1; CABP2; electrophysiology; inner ear; synapse; spiral ganglion neuron; neuroscience; ear; hearing; immunohistochemistry
 
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