Degeneration rates of cochlear hair cells and neurons in a DFNA2 deafness model

DIONISIO LEONARDO; CARIGNANO, CAMILA; BARILA, ESTEBAN PABLO; RIAS, EZEQUIEL; AZTIRIA, EUGENIO; SPITZMAUL GUILLERMO

Mar del Plata

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica

Potassium (K+) circulation is fundamental for a proper hearing function. Sound waves induce movements of basilar membrane inside the cochlear compartments, which open mechanotransduction channels. Since apical surface of hair cells is exposed to endolymph (high K+ concentration), the opening of these channels allows the entrance of K+ into the hair cells causing cell membrane depolarization. Immediately, K+ must be removed outside the cell to restore the membrane potential, otherwise it would continuously depolarize the cells and interfere with normal excitability. K+ extrusion is mediated in normal conditions mainly by voltage-gated potassium channel KCNQ41 in outer hair cells (OHCs) and Ca2+-activated potassium channel BK in inner hair cells (IHCs)2. KCNQ4 is mostly expressed in the basal membrane of outer hair cells (OHCs) but it was also detected at low levels in IHCs3,1 and some central nuclei of the auditory pathway4. Alterations in normal K+ circulation would lead to auditory malfunction. Hearing loss (HL) is one of the most common sensory deficits. According to the WHO, approximately 5% of world population suffer disabling HL defined as a deficiency in hearing capacity greater than 40 dB. HL may result from different causes: acquired, genetic or a combination of both. In many of these conditions, alterations of K+ circulation is observed at least in some stages. The most frequent acquired HL is the noise-induced hearing loss (NIHL), produced by overexposure to loud sounds, causing trauma to the ear, deteriorating hearing ability4. Among genetic ones, presbycusis, an age-related and progressive HL, is the most frequent. It is initially observed as a reduction in the capacity to hear high frequencies (>14 kHz)5. Another progressive HL is DFNA2, which is an inherited autosomal dominant disease. It affects numerous families from diverse backgrounds, including those of European, American, and Asian origins, thus demonstrating its genetic heterogeneity. It is a slow progressive HL characterized for starting at ages around 15-20 years-old with a mild to moderate hearing impairment and progressing to severe HL by the age of 706. Most of the cases are caused by mutations in the K+ channel KCNQ4, maintaining OHCs chronically depolarized and leading to impaired cell function and cell death. DFNA2 initially can be explained by loss of OHCs (increase in hearing sensibility up to 60 dB) but at later stages develops a deep hearing loss that cannot be explained only by death of OHCs, suggesting other mechanisms involved in the progression of the disease7.Transgenic mice with a deletion in Kcnq4 gene (Kcnq4-/-) develop a DFNA2-like HL syndrome. So, our aim is to study how the alteration in K+ circulation, induced by the absence of KCNQ4 channel, generates tissue degeneration.KCNQ4 channel absence impairs K+ extrusion from OHCs which would disturb K+ recycling in the inner ear, leading to OHC death and tissue degeneration in a few weeks1. Previous studies have been developed in a mouse strain that experiments a relatively high rate of age-related hearing loss (C57Bl/6), which impedes studies of cochlear degeneration in aging mice. For these reasons we backcrossed the Kcnq4- allele to a mouse strain (C3H) with very few HL even in old mouse (>1 year-old).To get new insights into to progression of the disease, we studied the survival of OHCs, IHCs and Spiral Ganglion Neurons (SGN) in the mouse lacking KCNQ4 expression and in their wild-type (WT) counterpart.