Age‐related changes in the biophysical and morphological characteristics of mouse cochlear outer hair cells

Abstract

Key points Age‐related hearing loss (ARHL) is a very heterogeneous disease, resulting from cellular senescence, genetic predisposition and environmental factors (e.g. noise exposure). Currently, we know very little about age‐related changes occurring in the auditory sensory cells, including those associated with the outer hair cells (OHCs). Using different mouse strains, we show that OHCs undergo several morphological and biophysical changes in the ageing cochlea. Ageing OHCs also exhibited the progressive loss of afferent and efferent synapses. We also provide evidence that the size of the mechanoelectrical transducer current is reduced in ageing OHCs, highlighting its possible contribution in cochlear ageing. Abstract Outer hair cells (OHCs) are electromotile sensory receptors that provide sound amplification within the mammalian cochlea. Although OHCs appear susceptible to ageing, the progression of the pathophysiological changes in these cells is still poorly understood. By using mouse strains with a different progression of hearing loss (C57BL/6J, C57BL/6NTac, C57BL/6NTacCdh23+, C3H/HeJ), we have identified morphological, physiological and molecular changes in ageing OHCs (9–12 kHz cochlear region). We show that by 6 months of age, OHCs from all strains underwent a reduction in surface area, which was not a sign of degeneration. Although the ageing OHCs retained a normal basolateral membrane protein profile, they showed a reduction in the size of the K+ current and non‐linear capacitance, a readout of prestin‐dependent electromotility. Despite these changes, OHCs have a normal Vm and retain the ability to amplify sound, as distortion product otoacoustic emission thresholds were not affected in aged, good‐hearing mice (C3H/HeJ, C57BL/6NTacCdh23+). The loss of afferent synapses was present in all strains at 15 months. The number of efferent synapses per OHCs, defined as postsynaptic SK2 puncta, was reduced in aged OHCs of all strains apart from C3H mice. Several of the identified changes occurred in aged OHCs from all mouse strains, thus representing a general trait in the pathophysiological progression of age‐related hearing loss, possibly aimed at preserving functionality. We have also shown that the mechanoelectrical transduction (MET) current from OHCs of mice harbouring the Cdh23ahl allele is reduced with age, highlighting the possibility that changes in the MET apparatus could play a role in cochlear ageing.

Pathophysiological changes in inner hair cell ribbon synapses in the ageing mammalian cochlea

“…2012; Zachary & Fuchs, 2015), was found to be correlated with the degree of hearing loss in the different mouse strains (Jeng et al . 2020 b ). The contribution of the MET current to the ageing hearing phenotype is supported by the observation that the structural and functional integrity of the stereociliary bundles is progressively altered with age (Bohne et al ., 1990; Bullen et al ., 2019) and that the hypomorphic Cdh23 ahl allele leads to early‐onset hearing loss in several inbred mouse strains such as 6J (C57BL/6J) and 6N (C57BL/6NTac) mice (e.g.…”

“…The dissection procedure of the aged mouse cochlea was performed as previously described (Jeng et al . 2020 b ). The excised cochleae were dissected in extracellular solution composed of (in m m ): 135 NaCl, 5.8 KCl, 1.3 CaCl 2 , 0.9 MgCl 2 , 0.7 NaH 2 PO 4 , 5.6 d ‐glucose, 10 Hepes‐NaOH.…”

Loss of Baiap2l2 destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness

“…For DPOAE experiments, as a result of the presence of 'not found' values (i.e. above the upper threshold limit of our equipment), the non-parametric aligned ranks transformation two-way ANOVA statistical test (Mann-Whitney U test for pairwise comparisons with Bonferroni adjusted P values) was used; data are quoted as median, as well as the first and third quartiles (see also: (Jeng et al 2020b).…”

Biophysical and morphological changes in inner hair cells and their efferent innervation in the ageing mouse cochlea

“…The pH was adjusted to 7.48 (∼308 mmol kg −1 ). The dissection procedure of the ageing mouse cochlea has been described previously (Jeng et al 2020a). After dissection the isolated organ of Corti was transferred to a microscope chamber, immobilized with a nylon mesh fixed to a stainless steel ring and viewed using an upright microscope (Olympus BX51, Japan; Leica, DMLFS, Germany; Nikon FN-1, Japan).…”

“…However, damage to the auditory receptors in the cochlea, namely the inner and outer hair cells (IHCs and OHCs) and their innervation, is likely to play a key role (Johnsson, 1974;Schuknecht & Gacek, 1993;Sergeyenko et al 2013;Tawfik et al 2019;Wu et al 2019;Jimenez et al 2020). Although we now have a better understanding of age-related changes in OHCs (Jeng et al 2020a) and IHC ribbon synapses (Jeng et al 2020b), very little is known about how the biophysical properties of IHCs and their efferent innervation are affected by cochlear ageing, which limits our understanding of how IHC function contributes to the progression of ARHL.…”