MOLECULAR ALTERATIONS CAUSED BY CHRONIC COCHLEAR DEPOLARIZATION IN A MOUSE MODEL OF HEARING LOSS

DIONISIO, LEONARDO; RIAS, EZEQUIEL; CARIGNANO, CAMILA; STUPNIKI, SOFIA; VERA, MARCELA; SPITZMAUL, GUILLERMO

Virtual

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2021; 2021

The voltage-gated potassium (K+) channel KCNQ4 is the main responsiblefor the extrusion of the K+ that enters the cochlear sensorycells upon sound stimulation. Besides, outer hair cells (OHC) excitabilityis under control of the efferent neurons of the Medial Olivocochlear(MOC) system. In response to overstimulation, MOC cholinergicneurons activate the calcium-induced K+ channels BK andSK2, which extrude K+ out of the cell repolarizing the membrane. Intracellularaccumulation of K+ leads to a chronic depolarization thatmay damage hair cells causing hearing loss (HL). KCNQ4 activityimpairment is the main cause of DFNA2, a non-syndromic progressiveHL. Using a mouse model lacking Kcnq4 (Kcnq4-/-), we reportedthat OHC death begins at the basal turn progressing to the apexin 3-6-week-old (W) animals. We hypothesized that the KCNQ4 absencecauses MOC chronic overstimulation leading to activation ofdeath pathways. Using immunofluorescence (IF), we evaluated theMOC terminals and observed a lower synaptic density and mislocalizationof the efferent terminals contacting OHC in 4W Kcnq4-/-mice. In addition, we analyzed by qPCR the gene expression of theefferent components located in the MOC terminals. We detected a~3.5-fold decrease in the mRNA expression of the nicotinic receptorα10 subunit with no changes in the α9 subunit, and a ~8-folddecrease in the mRNA expression of BK and SK2 in 4W Kcnq4-/-animals. Finally, we studied the possible pathways involved in OHCdeath. By IF, we found an increase of cleaved-caspase 3 expressionin the OHC at the basal turn and gene expression analysis by qPCRrevealed that the pro-apoptotic Bax transcript was upregulated whileanti-apoptotic Bcl2 was downregulated in Kcnq4-/- mice. These resultsdemonstrate an alteration of the efferent transmission in OHCthat could contribute to the activation of the apoptotic pathway drivingto OHC death.