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

Jeng, Jing‐Yi; Carlton, Adam J; Johnson, Stuart L.; Brown, Steve; Holley, Matthew C.; Bowl, Michael R.; Marcotti, Walter

doi:10.1113/jp280256

Cited by 30 publications

(54 citation statements)

References 76 publications

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“…Recent studies of aged OHCs are consistent with the idea that OHCs undergo a period of dysfunction prior to OHC loss. In a study of aged OHCs from early onset and late onset ARHL mouse models, Jeng and colleagues suggested that age-related OHC dysfunction is not due to apoptosis (Jeng et al 2021). They primarily focused their studies on OHCs from the 9-12kHz region.…”

Section: Discussionmentioning

confidence: 99%

“…With the exception of membrane voltage, they showed that these biophysical properties decreased similarly with age, being highest in the youngest animals. In addition to OHC loss, they found decreases in OHC size as indicated by decreases in membrane capacitance, OHC ribbons, and the mRNA expression of SIc26a5 and OCM (Jeng et al 2021). Most, if not all, of these features changed similarly, independent of the ARHL onset suggesting that they are general features of aging in OHCs, and not necessarily related to the OHC dysfunction observed in ARHL.…”

Section: Discussionmentioning

confidence: 99%

“…The underlying pathology is progressive loss of cochlear sensory cells mediated by intrinsic apoptosis especially in basal hair cells after 6 mo with complete loss of basal OHCs by 12 mo (Francis et al 2003, Li and Hultcrantz 1994, Someya et al 2009, Spongr et al 1997). Recently, Jeng and colleagues performed extensive analyses of the biophysical properties of aging inner and outer hair cells and their synapses in four genetic mouse strains with early or late ARHL onset (Jeng et al 2021, Jeng et al 2020a, Jeng et al 2020b). They concluded that alterations in the mechanoelectrical transducer (MET) in the stereocilia bundle and OHC efferent synapses possibly contribute to the progression of ARHL, and that apoptosis of sensory cells may not be a contributing factor.…”

Section: Introductionmentioning

confidence: 99%

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Oncomodulin Delays Age-Related Hearing Loss in C57 and CBA Mice

Murtha

et al. 2021

Preprint

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Ca2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca2+ binding protein preferentially expressed in outer hair cells of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM prevents early progressive hearing loss in mice of two different genetic backgrounds: CBA/CaJ and C57Bl/6J. In both backgrounds, genetic disruption of Ocm leads to early progressive hearing loss as measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). In both strains, loss of Ocm reduced hearing across lifetime (hearing span) by more than 50% relative to wild type (WT). Even though the two WT strains have very different hearing spans, OCM plays a considerable and similar role within their genetic environment to regulate hearing function. The accelerated ARHL of the Ocm KO illustrates the importance of Ca2+ signaling in maintaining hearing health.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oncomodulin Delays Age-Related Hearing Loss in C57 and CBA Mice

Murtha

et al. 2021

Preprint

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“…An L-glutamic acid based intracellular solution was used as it preserves cellular ultrastructure and improves the stability of recordings (Kay, 1992). A similar solution has extensively been used for investigating the biophysical properties of mammalian cochlear hair cells (e.g Corns et al 2018;Jeng et al 2020a;2020b).…”

Section: Whole Cell Patch Clampmentioning

confidence: 99%

MET currents and otoacoustic emissions from mice with a detached tectorial membrane indicate the extracellular matrix regulates Ca²⁺ near stereocilia

Jeng

Harasztosi

Carlton

et al. 2021

The Journal of Physiology

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mice affects the biophysical properties of cochlear outer hair cells (OHCs).  Tecta/Tectb-/mice have highly elevated hearing thresholds, but OHCs mature normally.  MET channel resting open probability (P o) in mature OHC in vitro is ~50% in endolymphatic [Ca 2+ ], resulting in a large standing depolarizing MET current that would allow OHCs to act optimally as electromotile cochlear amplifiers.  MET channel resting P o in vivo is also high in Tecta/Tectb-/mice, indicating the TM is unlikely to statically bias the hair bundles of OHCs.  Distortion product otoacoustic emissions (DPOAEs), a readout of active, MET-dependent, non-linear cochlear amplification in OHCs, fail to exhibit long-lasting adaptation to repetitive stimulation in Tecta/Tectb-/mice.  We conclude that during prolonged, sound-induced stimulation of the cochlea the TM may determine the extracellular Ca 2+ concentration near the OHC's MET channels.

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“…Ahl is a recessive single nucleotide mutation at 753 (G=>A) on the Cdh23 gene on mouse chromosome 10 (Noben-Trauth et al, 2003). Cdh23 encodes cadherin 23, a protein necessary for inner ear development and maintenance of the sensory hair cell structures, in particular the tip and lateral links of the stereocilia at the hair bundle (Siemens et al, 2004; Söllner et al, 2004; Kazmierczak et al, 2007; Michel et al, 2005; Lagziel et al, 2005), but growing anatomical evidence also suggests that synaptic rearrangements on sensory hair cells also contribute to auditory functional decline in C57BL/6J mice (Stamataki et al, 2006; Zachary and Fuchs, 2015; Jiang et al, 2015; Jeng et al, 2021). Surprisingly, aging C57BL/6J mice, although showing cochlear ribbon synapse degeneration and hearing loss, display increased acoustic startle reflex amplitudes (Ouagazzal et al, 2006; Ison and Allen, 2003; Ison et al, 2007) and a time increase in recovery from ABR short-term adaptation (Walton et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Synaptic Release Potentiation at Aging Auditory Ribbon Synapses

Peineau

Belleudy

Bouleau

et al. 2020

Preprint

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46Cochlear inner hair cells (IHCs) harbor a peculiar presynaptic organelle, the ribbon, which is 47 essential for aggregating synaptic vesicles and organizing Ca 2+ channels at the active zone. 48 Emerging evidence suggests that damage to the ribbon synapses represents an important form 49 of cochlear synaptopathy that seems prevalent in age-related sensorineural hearing loss. The 50 functional changes occurring at these synapses during aging are not fully understood. Here, 51 we characterized the age-related changes in IHCs of C57BL/6J mice, a strain which is known 52 to carry a cadherin23 mutation and experiences early hearing loss with age. We found a 53 progressive loss of synaptic ribbons with aging, starting before postnatal day 180 (P180) and 54 reaching up to 50 % loss in middle age mice at P365. A deletion of the Otof gene, encoding 55 the Ca 2+ sensor otoferlin produced an accelerated loss of IHC ribbons with aging, with a 50 % 56 loss by P60. In both Otof +/+ and Otof -/-C57BL/6J mice, the synaptic ribbons became larger 57 with aging and IHCs displayed a drastic cell surface reduction with a large decrease in 58 extrasynaptic BK-channel expression. These changes are indicative of oxidative stress and 59 synaptic autophagy as suggested by an increased expression of the autophagosomal protein 60 LC3B. Furthermore, whole-cell patch-clamp recordings and calcium imaging in IHCs from 61 old Otof +/+ P365 C57BL/6J mice indicated an increase in Ca 2+ -channel density and a stronger 62 exocytosis at the remaining ribbon active zones, suggesting synaptic release potentiation 63 possibly explaining hyperacusis and recruitment in the elderly.64 65 3 SIGNIFICANCE STATEMENT 66 67Age-related hidden hearing loss is often described as a cochlear synaptopathy that results 68 from a progressive degeneration of the ribbon synapses contacting the inner hair cells (IHCs). 69 We show that the auditory defect of aging C57BL/6J mice is associated with a large shrinkage 70 of IHCs and a drastic enlargement of their remaining presynaptic ribbons. Synaptic Ca 2+ 71 microdomains and exocytosis were largely increased in old IHCs, while on the contrary the 72 expression of the fast repolarizing BK channels, known to negatively control transmitter 73 release, was decreased. This age-related synaptic plasticity in IHCs suggested a functional 74 potentiation of synaptic transmission at the surviving synapses, a process that could partially 75 compensate the decrease in synapse number and underlie hyperacusis. 76 77 78 4 79 80 Age-related hearing loss (ARHL or presbycusis) is the most prevalent form of sensory 81 disability in human populations and adversely affects the quality of life of many elderly 82 individuals. The development of ARHL has been generally considered to be associated with 83 primary degeneration of cochlear hair cells, with secondary deafferentation associating 84 degeneration of spiral ganglion neurons and ribbon synapses. However, recent studies have 85 resulted in a paradigm shift in the understanding of ...

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

Cited by 30 publications

References 76 publications

Oncomodulin Delays Age-Related Hearing Loss in C57 and CBA Mice

Oncomodulin Delays Age-Related Hearing Loss in C57 and CBA Mice

MET currents and otoacoustic emissions from mice with a detached tectorial membrane indicate the extracellular matrix regulates Ca²⁺ near stereocilia

Synaptic Release Potentiation at Aging Auditory Ribbon Synapses

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

Cited by 30 publications

References 76 publications

Oncomodulin Delays Age-Related Hearing Loss in C57 and CBA Mice

Oncomodulin Delays Age-Related Hearing Loss in C57 and CBA Mice

MET currents and otoacoustic emissions from mice with a detached tectorial membrane indicate the extracellular matrix regulates Ca2+ near stereocilia

Synaptic Release Potentiation at Aging Auditory Ribbon Synapses

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Product

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MET currents and otoacoustic emissions from mice with a detached tectorial membrane indicate the extracellular matrix regulates Ca²⁺ near stereocilia