Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness

Abstract

KCNQ4 is an M-type K þ channel expressed in sensory hair cells of the inner ear and in the central auditory pathway. KCNQ4 mutations underlie human DFNA2 dominant progressive hearing loss. We now generated mice in which the KCNQ4 gene was disrupted or carried a dominant negative DFNA2 mutation. Although KCNQ4 is strongly expressed in vestibular hair cells, vestibular function appeared normal. Auditory function was only slightly impaired initially. It then declined over several weeks in Kcnq4 À/À mice and over several months in mice carrying the dominant negative allele. This progressive hearing loss was paralleled by a selective degeneration of outer hair cells (OHCs). KCNQ4 disruption abolished the I K,n current of OHCs. The ensuing depolarization of OHCs impaired sound amplification. Inner hair cells and their afferent synapses remained mostly intact. These cells were only slightly depolarized and showed near-normal presynaptic function. We conclude that the hearing loss in DFNA2 is predominantly caused by a slow degeneration of OHCs resulting from chronic depolarization.

Dominant-Negative Inhibition of M-Like Potassium Conductances in Hair Cells of the Mouse Inner Ear

“…Previous reports have suggested that the low-voltage activated potassium conductance, termed G K,n , first identified in guinea pig outer hair cells (Housley and Ashmore, 1992), consists of KCNQ4 subunits Marcotti and Kros, 1999;Trussell, 2000;Kharkovets et al, 2000Kharkovets et al, , 2006. Furthermore, Beisel et al (2000Beisel et al ( , 2005 have noted a temporal correlation between the physiological expression of G K,n and the molecular expression of KCNQ4, both following an apical to basal expression pattern.…”

“…Furthermore, Beisel et al (2000Beisel et al ( , 2005 have noted a temporal correlation between the physiological expression of G K,n and the molecular expression of KCNQ4, both following an apical to basal expression pattern. Previously, Kharkovets et al (2006) also showed a lack of G K,n expression in KCNQ4 knock-out mice. To verify the link between G K,n and KCNQ4 and the effectiveness of our dominant-negative adenoviral vector approach, we generated cochlear explants cultures and applied Ad1-cmv-hKCNQ4-G285S directly to the culture media.…”

“…As a result, identification of the molecular substrate for each conductance has not been trivial. For example, although there is substantial evidence for KCNQ4 expression in hair cells (Kubisch et al, 1999;Beisel et al, 2000Beisel et al, , 2005Kharkovets et al, 2000Kharkovets et al, , 2006Hurley et al, 2006;RochaSanchez et al, 2007), identification of its physiological correlate has been confounded by the significant difference between the biophysical properties of KCNQ4 expressed in heterologous cells and those of hair-cell potassium conductances. In heterologous cells, KCNQ4 expression results in large, slowly activating, noninactivating currents with broad voltage dependence centered around Ϫ20 to Ϫ30 mV (Kubisch et al, 1999;Schroder et al, 2001;Sogaard et al, 2001;Hougaard et al, 2004;Chambard and Ashmore, 2005).…”

The Role of BKCa Channels in Electrical Signal Encoding in the Mammalian Auditory Periphery

“…Furthermore, depolarization may drive Ca v channels into inactivation and thus decrease the Ca 2ϩ currents that drive transmission. However, Kharkovets et al (2006) recently reported that weak depolarization did not appreciably reduce IHC Ca 2ϩ currents. Alternatively, IHC depolarization may lead to an increased percentage of transducer channels open at rest because of reduced Ca 2ϩ influx (Assad et al, 1989;Kennedy et al, 2003).…”

An in vitro model system to study gene therapy in the human inner ear

“…7 In mice, KCNQ4 has been shown to be expressed exclusively in the auditory and vestibular systems, and in particular, in auditory and vestibular hair cells. 10,45 Furthermore, it has been suggested that potassium channels that consist of KCNQ4 subunits carry the ionic currents known as I K,n and I K,L in auditory and vestibular hair cells, respectively. 9 We found robust expression of KCNQ4 in human hair cells, including type I cells.…”