Role of KCNQ4 and KCNQ5 K+ channels in the vestibular organ

Abstract

The vestibular organ provides essential sensory input for the control of body equilibrium, head orientation and eye movements. Sensory hair cells (HCs), named type I and type II, are located in the otholithic organs (utricle and saccule) and cristae ampullaris. HCs are distinguished by their distinctive pattern of innervation and also by the distinctive plasma membrane currents. The electrical output of the vestibular organ depends on the mechanosensitive cation channels of their stereocilia and on the sum of other ion channels present in HCs and their innervating neurons whose cell bodies are located in the vestibular ganglion. Two members of the KCNQ (Kv7) family of voltage-gated K+ -channels are expressed in the vestibular organ, KCNQ4 and KCNQ5. KCNQ4 is best known for its role in hearing and touch sensation and is mutated in patients with slowly progressive hearing loss of the DFNA2 type. KCNQ5 is also expressed in vestibular sensory epithelia. So far, no human disease caused by Kcnq5 mutations has been described. In this work, we determine in detail the expression pattern of KCNQ4 and KCNQ5 in the vestibular system, ask whether they contribute to vestibular HC currents and examine their role in the function of the vestibular system. To this end we used mouse models lacking expression of KCNQ4 (KCNQ4-/- ), expressing a dominant negative mutation of KCNQ5 (KCNQ5dn/dn ) or a combi- nation of both genetic modifications (KCNQ4-/- ;KCNQ5dn/dn ). We performed immunofluorescence, patch-clamp and vestibulo-ocular reflex (VOR) measurements to analyze them. Surprisingly and contrasting with KCNQ4 in cochlear outer hair cells, neither channel is significantly expressed in adult vestibular HCs, but rather postsynaptically in calyx synapses of vestibular neurons innervating these cells. Accordingly, currents of vestibular HCs are unchanged upon the disruption of their genes. Calyx expression of KCNQ4 is high in the central zone of the cristae and striola of the utricle/ saccule and low in the rest of the organs while KCNQ5 is only expressed in the peripheral zone of cristae and extrastriolar region. Preliminary behavioural experiments showed a vestibular phenotype in the double transgenic mice. Thus, KCNQ4 and five are important for a proper coding of the electric signals in calyx endings of vestibular neurons and mouse models would allow functional analysis of vestibular organ regions.