Synaptic migration and reorganization after noise exposure suggests regeneration in a mature mammalian cochlea

Hickman, Tyler; Hashimoto, Ken; Liberman, Leslie D.; Liberman, M. Charles

doi:10.1038/s41598-020-76553-w

Cited by 50 publications

(60 citation statements)

References 43 publications

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“…At the same time, high activity rates such as those that occur during acoustic overexposure may render this unmyelinated small-volume segment of the ANF within the organ of Corti vulnerable to ionic imbalance (Figure 1C). Immediately after a 90-min exposure to 4-8 kHz octave band noise at 109 dB SPL, we observed some dendritic fragmentation between the ribbon synapses in the inner spiral plexus (ISP) and the heminodes at the habenula perforata (HP, vertical arrowheads), consistent with synapse loss and osmotic damage seen after synaptopathic noise exposure in confocal and electron microscopy that can be blocked with the glutamate receptor antagonist kynurenic acid (Robertson, 1983;Puel et al, 1998;Furman et al, 2013;Hickman et al, 2020).…”

Section: Introductionsupporting

confidence: 64%

“…This noise-induced cochlear synaptopathy is a form of excitotoxicity that appears to depend on synaptic release of glutamate from inner hair cells (IHCs), as demonstrated in the vesicular glutamate transporter type-3 (Vglut3) knockout mouse (Kim et al, 2019 ). In the guinea pig, synaptopathic noise exposure resulted in synaptic reorganization, impaired temporal processing, and selective reduction in the proportion of ANFs with the low-spontaneous rate/high-threshold phenotype thought to be important for the encoding of suprathreshold sounds in noisy environments (Furman et al, 2013 ; Shi et al, 2013 ; Hickman et al, 2020 ). Higher doses of noise can result in cochlear synaptopathy accompanied by immediate loss of outer hair cells and permanent threshold shifts (Fernandez et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors

Walia

Lee

Hartsock

et al. 2021

Front. Synaptic Neurosci.

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Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca2+ permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca2+-permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca2+-impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h in vitro, and elimination half-lives in vivo of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC50 ~ 73 μM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection.

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Section: Introductionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors

Walia

Lee

Hartsock

et al. 2021

Front. Synaptic Neurosci.

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“…Unlike young P30 IHCs, old P365 IHCs had modiolar and pillar ribbons with similar volume (0.7 ± 0.1 μm 3 and 0.57 ± 0.07 μm 3 , respectively; not significantly different, unpaired t-test p = 0.28, Fig.4D). Similar preferential loss of synaptic modiolar ribbons associated with an increase in ribbon volume was also reported after noise-induced hearing loss (Liberman and Kujawa, 2017; Hickman et al, 2020).…”

Section: Resultssupporting

confidence: 78%

“…Image resolution was 0.038 μm/pixel. As previously described by Hickman et al (2020) and Jeng et al, (2020), the x,y,z coordinates of ribbons in each z-stack were transformed into a coordinate system based on the modiolar-pillar polarity of the IHCs. We determined the pillar versus modiolar distribution of the synaptic ribbons by using a k- means clustering method in the z-stack position of each ribbon, with arbitrarily choosing the number of cluster as 2 (OriginPro 9.1software, OriginLab, Northampton, USA).…”

Section: Methodsmentioning

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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“…The phenomenon of noise-induced and/or age-related primary cochlear neural degeneration has been documented in mice (Kujawa and Liberman, 2009 ; Sergeyenko et al, 2013 ), guinea pigs (Lin et al, 2011 ; Furman et al, 2013 ), chinchillas (Hickox et al, 2017 ; Hickman et al, 2018 ), gerbils (Gleich et al, 2016 ), rats (Lee et al, 2021 ) and rhesus macaques (Valero et al, 2017 ), as well as in humans (Wu et al, 2019 , 2021 ). However, species and even strain differences in the permanence of noise-induced losses have been reported (Shi et al, 2013 ; Wang et al, 2015 ; Kaur et al, 2019 ; Hickman et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Noise-Induced Hearing Loss in Gerbil: Round Window Assays of Synapse Loss

Jeffers

Bourien

Diuba

et al. 2021

Front. Cell. Neurosci.

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Previous work in animals with recovered hearing thresholds but permanent inner hair cell synapse loss after noise have suggested initial vulnerability of low spontaneous rate (SR) auditory nerve fibers (ANF). As these fibers have properties of response that facilitate robust sound coding in continuous noise backgrounds, their targeted loss would have important implications for function. To address the issue of relative ANF vulnerabilities after noise, we assessed cochlear physiologic and histologic consequences of temporary threshold shift-producing sound over-exposure in the gerbil, a species with well-characterized distributions of auditory neurons by SR category. The noise exposure targeted a cochlear region with distributed innervation (low-, medium- and high-SR neurons). It produced moderate elevations in outer hair cell-based distortion-product otoacoustic emission and whole nerve compound action potential thresholds in this region, with accompanying reductions in suprathreshold response amplitudes, quantified at 24 h. These parameters of response recovered well with post-exposure time. Chronic synapse loss was maximum in the frequency region initially targeted by the noise. Cochlear round window recorded mass potentials (spontaneous neural noise and sound-driven peri-stimulus time responses, PSTR) reflected parameters of the loss not detected by the conventional assays. Spontaneous activity was acutely reduced. Steady-state (PSTR plateau) activity was correlated with synapse loss in frequency regions with high concentrations of low-SR neurons, whereas the PSTR onset peak and spontaneous round window noise, both dominated by high-SR fiber activity, were relatively unaltered across frequency in chronic ears. Together, results suggest that acute targets of noise were of mixed SR subtypes, but chronic targets were predominantly low-SR neurons. PSTRs captured key properties of the auditory nerve response and vulnerability to injury that should yield important diagnostic information in hearing loss etiologies producing cochlear synaptic and neural loss.

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Synaptic migration and reorganization after noise exposure suggests regeneration in a mature mammalian cochlea

Cited by 50 publications

References 43 publications

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors

Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors

Synaptic Release Potentiation at Aging Auditory Ribbon Synapses

Noise-Induced Hearing Loss in Gerbil: Round Window Assays of Synapse Loss

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