Exploring MOC System Influence on OHC Degeneration in DFNA2-Related Deafness

RIAS E.; OUWERKERK I.; STUPNIKI, S.; PAOLILLO G.; CASTAGNA V.; BALLESTERO J.; DIONISIO, L.; ELGOYHEN A.; GOMEZ-CASATI E.; SPITZMAUL, G.

San Luis

Congreso; SAN Annual Congress; 2023

SAN

DFNA2, a form of progressive deafness linked to mutations within the voltage-gated potassium channel KCNQ4, exhibit chronic depolarization of outer hair cells (OHC) culminating in hearing loss. The efferent cholinergic neurons of the Medial Olivocochlear (MOC) system regulate OHC excitability by activating additional potassium channels (BK and SK2). This action aids KCNQ4 in restoring the cell’s membrane potential. To determine whether the efferent system can mitigate the tissue degeneration observed in a DFNA2 mouse model, a genetic approach was employed to enhance MOC potency. We merge this model with one exhibiting increased efferent tone Kcnq4-/-//Chrnα9L9´T/L9´T (KO-KI). Cochleae from both KO-KI and their respective WT-WT controls, aged 4 weeks, were dissected for immunostaining to elucidate tissue characteristics. We found a marked ~46% reduction in OHC count along the cochlear length in KO-KI mice compared to WT-WT, with no variation in inner hair cell numbers. By confocal imaging, we studied the location of MOC terminals in OHC for both genotypes: KO-KI displayed a ~14% mislocalization, an anomaly absence in WT-WT mice. Furthermore the number of synaptic terminals per OHC was ~30% lower in KO-KI mice, accompanied by a ~24% reduction in their volume. These findings suggest that increasing MOC system activity might not reduce OHC loss in DFNA2-related deafness. This could be due to excessive calcium influx, potentially increasing the OHC stress.