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

DIONISIO, L.; CARIGNANO, C.; BARILA, E.P.; RIAS, E.; AZTIRIA, E.; SPITZMAUL, G.

Mar del Plata

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

SAIC-SAI_SAFIS2018

DFNA2, an autosomal dominant disease with progressive hearing loss, is caused by mutations in voltage-activated potassium channel KCNQ4. In DFNA2, Inner and Outer Hair Cells (IHC and OHC) remain chronically depolarized leading to impaired cell function, cell death and hearing loss. Transgenic mice with a deletion in Kcnq4 gene (Kcnq4-/-) develop a DFNA2-like hearing loss syndrome.Our aim is to characterize the degeneration rate of HCs and spiral ganglion neurons (SGN) in Kcnq4-/- mouse as a model of DFNA2.First, we evaluated mRNA and protein expression of KCNQ4, in different cochlear segments in wild-type (WT) mice. We observed lower expression in apical turn than in basal/middle ones (p=0.0035).Next, we evaluated HCs survival for WT and Kcnq4-/- mice. We constructed cytocochleograms at each age (3-58 postnatal weeks (W)), in which the HCs number in each 5%-segment of cochlear length was plotted relative to their distance from the apex. We observed that, for IHC and OHC, cell death began at basal turn increasing towards the apex with age in Kcnq4-/- mice. Moreover, cell death rate was slower in apical than in basal segments (p=0.0022), but started 30 weeks earlier in OHC than in IHC. Furthermore, using scanning electron microscopy, we observed that in Kcnq4-/- mice, cell degeneration became apparent in basal segments early at 4W, showing hair bundle disorganization an absence of OHCs.Finally, we analysed SGN survival in both genotypes in each segment at different ages. Kcnq4-/- animals showed neuronal loss starting at 40W for basal and apical segments (p