Key pointsr Outer hair cells (OHCs) enhance the sensitivity and the frequency tuning of the mammalian cochlea.r Similar to the primary sensory receptor, the inner hair cells (IHCs), the mature functional characteristics of OHCs are acquired before hearing onset.r We found that OHCs, like IHCs, fire spontaneous Ca 2+ -induced action potentials (APs) during immature stages of development, which are driven by Ca V 1.3 Ca 2+ channels.r We also showed that the development of low-and high-frequency hair cells is differentially regulated during pre-hearing stages, with the former cells being more strongly dependent on experience-independent Ca 2+ action potential activity.Abstract 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 Ca 2+ activity in the immature cochlea, which is generated by Ca V 1.3 Ca 2+ 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 Ca 2+ action potentials (APs), but only duringThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 152 J.-Y. Jeng and others J Physiol 598.1the first few postnatal days. Genetic ablation of these APs in vivo, using Ca V 1.3 −/− mice, prevented the normal developmental acquisition of mature-like basolateral membrane currents in low-frequency (apical) hair cells, such as I K,n (carried by KCNQ4 channels), I SK2 and I ACh (α9α10nAChRs) in OHCs and I K,n and I K,f (BK channels) in IHCs. Electromotility and prestin expression in OHCs were normal in Ca V 1.3 −/− mice. The maturation of high-frequency (basal) hair cells was also affected in Ca V 1.3 −/− mice, but to a much lesser extent than apical cells. However, a characteristic feature in Ca V 1.3 −/− 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 Ca 2+ APs.
Mechanoelectrical transduction at auditory hair cells requires highly specialized stereociliary bundles that project from their apical surface, forming a characteristic graded 'staircase' structure. r The morphogenesis and maintenance of these stereociliary bundles is a tightly regulated process requiring the involvement of several actin-binding proteins, many of which are still unidentified. r We identify a new stereociliary protein, the I-BAR protein BAIAP2L2, which localizes to the tips of the shorter transducing stereocilia in both inner and outer hair cells (IHCs and OHCs). r We find that Baiap2l2 deficient mice lose their second and third rows of stereocilia, their mechanoelectrical transducer current, and develop progressive hearing loss, becoming deaf by 8 months of age. r We demonstrate that BAIAP2L2 localization to stereocilia tips is dependent on the motor protein MYO15A and its cargo EPS8. r We propose that BAIAP2L2 is a new key protein required for the maintenance of the transducing stereocilia in mature cochlear hair cells.
(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/317172 doi: bioRxiv preprint first posted online May. 8, 2018; 3 adult cochlea (Guinan, 1996). However, OHCs are also innervated by Type II afferent fibres 49 that, unlike the Type I fibres contacting IHCs, which encode sound timing, intensity and 62We found that during a narrow, critical period of postnatal development, OHCs fire 63 spontaneous Ca 2+ spikes immediately preceding their functional maturation (~P7-P8 (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/317172 doi: bioRxiv preprint first posted online May. 8, 2018; 4 Results 70The functional development of OHCs was studied primarily in the apical third of the Figure 1C, Movie 1) and room temperature (~20°C: Figure 1D (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.)The copyright holder for this preprint . http://dx.doi.org/10.1101/317172 doi: bioRxiv preprint first posted online May. 8, 2018; 5 stopping a couple of days later ( Figure 1F). This correlated with a decrease in the maximum 95 Ca 2+ -related changes in fluorescence intensity (ΔF/F 0 ) for Ca 2+ measured from active OHCs 96( Figure `1G), which could be due to a progressive reduction of AP bursts with age. 97Calcium transients were abolished in Ca 2+ free solution (Figure 2A, Figure 3C, Movie 5). We quantified the average correlation 119All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. OHCs ( Figure 3D). However, the r s was independent of the amplitude (ΔF/F 0 ) of the Ca 2+ 127 signal ( Figure 3E) measured as a pixel average over the entire spread of the Ca 2+ wave. 128Therefore, the coordination of the electrical activity between nearby OHCs was dependent on 129 the lateral spread, but not the amplitude, of the Ca 2+ waves. 130We then sought to identify how spontaneous Ca 2+ activity from the non-sensory cells of the easier to see that the Ca 2+ waves originating in the GER were able to travel to the LER and 140propagate through Deiters' cells ( Figure 4D; Supplementary Figure 1B). In order to test 141whether Deiters' cells mediate signal transfer from the GER to the OHCs, we analysed Ca 2+ 142 signals after removal of Deiters' cells ( Figure 5C), which was performed using gentle suction 143 via a small pipette (~3-4 µm in diameter). This procedure is widely used to gain access to the 144 All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. OHCs ( Figure 5A,B, Movie 6). We found that Ca 2+ elevation in OHCs associated ...
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