K_v7-type channel currents in spiral ganglion neurons: Involvement in sensorineural hearing loss

Alterations in K_v7-mediated currents in excitable cells result in several diseased conditions. A case in DFNA2, an autosomal dominant version of progressive hearing loss, involves degeneration of hair cells and spiral ganglion neurons (SGNs) from basal to apical cochlea, manifesting as high-to-low frequency hearing loss, and has been ascribed to mutations in K_v7.4 channels. Analyses of the cellular mechanisms of K_v7.4 mutations and progressive degeneration of SGNs have been hampered by the paucity of functional data on the role K_v7 channels play in young and adult neurons. To understand the cellular mechanisms of the disease in SGNs, we examined temporal (young, 0.5 months old, and senescent, 17 months old) and spatial (apical and basal) roles of K_v7-mediated currents.Wereport that differential contribution of K_v7 currents in mice SGNs results in distinct and profound variations of the membrane properties of basal versus apical neurons. The current produces a major impact on the resting membrane potential of basal neurons. Inhibition of the current promotes membrane depolarization, resulting in activation of Ca²⁺ currents and a sustained rise in intracellular Ca²⁺. Using TUNEL assay, we demonstrate that a sustained increase in intracellular Ca²⁺ mediated by inhibition of K_v7 current results in significant SGN apoptotic death. Thus, this study provides evidence of the cellular etiology and mechanisms of SGN degeneration in DFNA2.