Hair cell maturation is differentially regulated along the tonotopic axis of the mammalian cochlea

Sound amplification within the mammalian cochlea depends upon specialized hair cells, the outer hair cells (OHCs), which possess both sensory and motile capabilities. In various altricial rodents, OHCs become functionally competent from around postnatal day 7 (P7), before the primary sensory inner hair cells (IHCs), which become competent at about the onset of hearing (P12). The mechanisms responsible for the maturation of OHCs and their synaptic specialization remain poorly understood. We report that spontaneous Ca2+ activity in the immature cochlea, which is generated by CaV1.3 Ca2+ channels, differentially regulates the maturation of hair cells along the cochlea. Under near‐physiological recording conditions we found that, similar to IHCs, immature OHCs elicited spontaneous Ca2+ action potentials (APs), but only during the first few postnatal days. Genetic ablation of these APs in vivo, using CaV1.3−/− mice, prevented the normal developmental acquisition of mature‐like basolateral membrane currents in low‐frequency (apical) hair cells, such as IK,n (carried by KCNQ4 channels), ISK2 and IACh (α9α10nAChRs) in OHCs and IK,n and IK,f (BK channels) in IHCs. Electromotility and prestin expression in OHCs were normal in CaV1.3−/− mice. The maturation of high‐frequency (basal) hair cells was also affected in CaV1.3−/− mice, but to a much lesser extent than apical cells. However, a characteristic feature in CaV1.3−/− mice was the reduced hair cell size irrespective of their cochlear location. We conclude that the development of low‐ and high‐frequency hair cells is differentially regulated during development, with apical cells being more strongly dependent on experience‐independent Ca2+ APs

The influence of non-sensory cells on the development of mammalian inner hair cells.

Immature auditory inner hair cells in the mammalian inner ear are capable of firing spontaneous calcium-dependent action potentials, which are required for their maturation into sensory receptors (Johnson et al., 2013; Johnson et al., 2017). Recent studies revealed that non-sensory cells can regulate the frequency and synchroneity of the action potentials among nearby inner hair cells by depolarizing them with ATP released through connexin hemichannels (Tritsch et al., 2007; Tritsch & Bergles, 2010). Nevertheless, the released ATP also induces a secondary potassium release from non-sensory cells, which was reported to depolarize the inner hair cells, thus synchronising their electrical activity (Tritsch et al., 2007; Tritsch & Bergles, 2010; Wang & Bergles, 2015). TMEM16A knockout mice were shown to prevent the potassium release from non-sensory cells and thus reduce the action potential activity in the inner hair cells (Wang & Bergles, 2015). In this study, I used the Cre-induction system to conditionally knockout TMEM16A in the non-sensory cells of the mouse cochlea, which allowed me to study the influence of TMEM16A-mediated potassium release on the action potential activity in the inner hair cells and their maturation. The results indicated that the absence of TMEM16A decreased the frequency and synchroneity of action potentials in immature inner hair cells without changing their spontaneous excitability. However, the influence from TMEM16A might not directly participate in the regulation of the maturing process of the inner hair cells