Voltage‐Gated Na⁺ Channel Activation Induces Both Action Potentials in Utricular Hair Cells and Brain‐Derived Neurotrophic Factor Release in the Rat Utricle During a Restricted Period of Development

Abstract

The mammalian utricular sensory receptors are commonly believed to be non‐spiking cells with electrical activity limited to graded membrane potential changes. Here we provide evidence that during the first post‐natal week, the sensory hair cells of the rat utricle express a tetrodotoxin (TTX)‐sensitive voltage‐gated Na+ current that displays most of the biophysical and pharmacological characteristics of neuronal Na+ current. Single‐cell RT‐PCR reveals that several α‐subunit isoforms of the Na+ channels are co‐expressed within a single hair cell, with a major expression of Nav1.2 and Nav1.6 subunits. In neonatal hair cells, 30 % of the Na+ channels are available for activation at the resting potential. Depolarizing current injections in the range of the transduction currents are able to trigger TTX‐sensitive action potentials. We also provide evidence of a TTX‐sensitive activity‐dependent brain‐derived neurotrophic factor (BDNF) release by early post‐natal utricle explants. Developmental analysis shows that Na+ currents decrease dramatically from post‐natal day 0 (P0) to P8 and become almost undetectable at P21. Concomitantly, depolarizing stimuli fail to induce both action potential and BDNF release at P20. The present findings reveal that vestibular hair cells express neuronal‐like TTX‐sensitive Na+ channels able to generate Na+‐driven action potentials only during the early post‐natal period of development. During the same period an activity‐dependent BDNF secretion by utricular explants has been demonstrated. This could be an important mechanism involved in vestibular sensory system differentiation and synaptogenesis.

Control of Hair Cell Excitability by Vestibular Primary Sensory Neurons

“…This developmental excitability, also observed in the mouse utricle (Geleoc et al, 2004), has also been reported in other sensory organs of the higher vertebrates, such as the cochlea (Evans and Fuchs, 1987;Kros et al, 1998) and the retina (Pan and Hu, 2000;Kawai et al, 2001). Although, in most cases, the physiological relevance of the I Na remains unknown, we first reported that I Na was involved in the activity-dependent secretion of brain-derived neurotrophic factor (BDNF) in the neonate rat utricle (Chabbert et al, 2003). Regarding the major role of BDNF in the establishment and the stabilization of synaptic contacts (Ernfors et al, 1995;Schimmang et al, 1995), we proposed that the transient hair cell excitability may contribute to the synaptogenesis process in the vestibular organs.…”

“…We have previously shown that, at birth [postnatal day 0 (P0)], rat utricle hair cells transiently express a neuronal-like tetrodotoxin (TTX)-sensitive voltage-gated Na ϩ current (I Na ), enabling these cells to generate sodium-driven action potentials (APs) (Chabbert et al, 2003). I Na is downregulated during the first postnatal week, decreasing the sodium-based excitability in mature hair cells.…”

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

“…We did not see the mixed Ca 2+ -Na + spikes that are typical of mouse IHCs in the first postnatal week (Marcotti et al, 2003b). All Atoh1 + cells lacked the voltage-gated Na + currents of immature HC subtypes (Chabbert et al, 2003;Eckrich et al, 2012;Géléoc et al, 2004;Li et al, 2010;Marcotti et al, 2003b;Oliver et al, 1997;Witt et al, 1994;Wooltorton et al, 2007). Again, these channels either were never expressed or had stopped being expressed by the earliest time point we examined, 12 days of in vitro differentiation.…”

Survival of Partially Differentiated Mouse Embryonic Stem Cells in the Scala Media of the Guinea Pig Cochlea

“…It is therefore likely that ES cell types will have to be cotransplanted with appropriate factors to encourage directed differentiation and integration. It is known that neurotrophic factors are important for hair cell development (Chabbert et al 2003), and a recent report indicates that epidermal growth factor (EGF) may be required to induce formation of new hair cells (Doetzlhofer et al 2004). The formation of new hair cells may also require overexpression of Math1, a transcription factor downstream in the EGF pathway that is essential for hair cell development (Zheng and Gao 2000;Woods et al 2004).…”