scholarly journals Synaptic Release Potentiation at Aging Auditory Ribbon Synapses

2021 ◽  
Vol 13 ◽  
Author(s):  
Thibault Peineau ◽  
Séverin Belleudy ◽  
Susanna Pietropaolo ◽  
Yohan Bouleau ◽  
Didier Dulon
Keyword(s):  
Hearing Loss ◽  
Acoustic Startle ◽  
Auditory Brainstem ◽  
Bk Channels ◽  
Acoustic Startle Reflex ◽  
Inner Hair Cell ◽  
Functional Changes ◽  
Ribbon Synapses ◽  
Age Related ◽  
Cadherin 23

Age-related hidden hearing loss is often described as a cochlear synaptopathy that results from a progressive degeneration of the inner hair cell (IHC) ribbon synapses. The functional changes occurring at these synapses during aging are not fully understood. Here, we characterized this aging process in IHCs of C57BL/6J mice, a strain which is known to carry a cadherin-23 mutation and experiences early hearing loss with age. These mice, while displaying a large increase in auditory brainstem thresholds due to 50% loss of IHC synaptic ribbons at middle age (postnatal day 365), paradoxically showed enhanced acoustic startle reflex suggesting a hyperacusis-like response. The auditory defect was associated with a large shrinkage of the IHCs' cell body and a drastic enlargement of their remaining presynaptic ribbons which were facing enlarged postsynaptic AMPAR clusters. Presynaptic Ca2+ microdomains and the capacity of IHCs to sustain high rates of exocytosis were largely increased, while on the contrary the expression of the fast-repolarizing BK channels, known to negatively control transmitter release, was decreased. This age-related synaptic plasticity in IHCs suggested a functional potentiation of synaptic transmission at the surviving synapses, a process that could partially compensate the decrease in synapse number and underlie hyperacusis.

scholarly journals Loss of Cochlear Ribbon Synapse Is a Critical Contributor to Chronic Salicylate Sodium Treatment-Induced Tinnitus without Change Hearing Threshold

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Zhang ◽  
Zhe Peng ◽  
ShuKui Yu ◽  
Qing-Ling Song ◽  
Teng-Fei Qu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Hearing Threshold ◽  
Significant Loss ◽  
Acoustic Startle Reflex ◽  
Ribbon Synapse ◽  
Inner Hair Cell ◽  
Adult Rats ◽  
Ribbon Synapses

Tinnitus is a common auditory disease worldwide; it is estimated that more than 10% of all individuals experience this hearing disorder during their lifetime. Tinnitus is sometimes accompanied by hearing loss. However, hearing loss is not acquired in some other tinnitus generations. In this study, we injected adult rats with salicylate sodium (SS) (200 mg/kg/day for 10 days) and found no significant hearing threshold changes at 2, 4, 8, 12, 14, 16, 20, or 24 kHz (all p>0.05). Tinnitus was confirmed in the treated rats via Behaviour Testing of Acoustic Startle Response (ASR) and Gap Prepulse Inhibition Test of Acoustic Startle Reflex (GPIAS). A immunostaining study showed that there is significant loss of anti-CtBP2 puncta (a marker of cochlear inner hair cell (HC) ribbon synapses) in treated animals in apical, middle, and basal turns (all p<0.05). The ABR wave I amplitudes were significantly reduced at 4, 8, 12, 14, 16, and 20 kHz (all p<0.05). No significant losses of outer HCs, inner HCs, or HC cilia were observed (all p>0.05). Thus, our study suggests that loss of cochlear inner HC ribbon synapse after SS exposure is a contributor to the development of tinnitus without changing hearing threshold.

scholarly journals Presynaptic plasticity at ageing auditory ribbon synapses: enlarged synaptic ribbons with increased Ca2+ microdomains and reduced BK channel clusters

2020 ◽  
Author(s):  
Thibault Peineau ◽  
Séverin Belleudy ◽  
Yohan Bouleau ◽  
Didier Dulon
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
The Elderly ◽  
Bk Channels ◽  
Bk Channel ◽  
Synaptic Ribbons ◽  
Inner Hair Cells ◽  
Functional Changes ◽  
Ribbon Synapses ◽  
Age Related

ABSTRACTCochlear inner hair cells (IHCs) harbor a peculiar presynaptic organelle, the ribbon, which is essential for aggregating synaptic vesicles and organizing Ca2+ channels at the active zone. Emerging evidence suggests that damage to the ribbon synapses represents an important form of cochlear synaptopathy that seems prevalent in age-related sensorineural hearing loss. The functional changes occurring at these synapses during aging are not fully understood. Here, we characterized the age-related changes in IHCs of C57BL/6J mice, a strain which is known to carry a cadherin23 mutation and experiences early hearing loss with age. We found a progressive loss of synaptic ribbons with aging, starting before postnatal day 180 (P180) and reaching up to 50 % loss in middle age mice at P365. A deletion of the Otof gene, encoding the Ca2+ sensor otoferlin produced an accelerated loss of IHC ribbons with aging, with a 50 % loss by P60. In both Otof+/+ and Otof-/- C57BL/6J mice, the synaptic ribbons became larger with aging and IHCs displayed a drastic cell surface reduction with a large decrease in extrasynaptic BK-channel expression. These changes are indicative of oxidative stress and synaptic autophagy as suggested by an increased expression of the autophagosomal protein LC3B. Furthermore, whole-cell patch-clamp recordings and calcium imaging in IHCs from old Otof+/+ P365 C57BL/6J mice indicated an increase in Ca2+-channel density and a stronger exocytosis at the remaining ribbon active zones, suggesting synaptic release potentiation possibly explaining hyperacusis and recruitment in the elderly.SIGNIFICANCE STATEMENTAge-related hidden hearing loss is often described as a cochlear synaptopathy that results from a progressive degeneration of the ribbon synapses contacting the inner hair cells (IHCs). We show that the auditory defect of aging C57BL/6J mice is associated with a large shrinkage of IHCs and a drastic enlargement of their remaining presynaptic ribbons. Synaptic Ca2+ microdomains and exocytosis were largely increased in old IHCs, while on the contrary the expression of the fast repolarizing BK channels, known to negatively control transmitter release, was decreased. This age-related synaptic plasticity in IHCs suggested a functional potentiation of synaptic transmission at the surviving synapses, a process that could partially compensate the decrease in synapse number and underlie hyperacusis.

scholarly journals N-Methyl-D-Aspartate Receptors Involvement in the Gentamicin-Induced Hearing Loss and Pathological Changes of Ribbon Synapse in the Mouse Cochlear Inner Hair Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Juan Hong ◽  
Yan Chen ◽  
Yanping Zhang ◽  
Jieying Li ◽  
Liujie Ren ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Auditory Brainstem ◽  
Ribbon Synapse ◽  
Synaptic Ribbons ◽  
Pathological Changes ◽  
Inner Hair Cell ◽  
Ribbon Synapses ◽  
Brainstem Response ◽  
Mature Mouse ◽  
Response Thresholds

Cochlear inner hair cell (IHC) ribbon synapses play an important role in sound encoding and neurotransmitter release. Previous reports show that both noise and aminoglycoside exposures lead to reduced numbers and morphologic changes of synaptic ribbons. In this work, we determined the distribution of N-methyl-D-aspartate receptors (NMDARs) and their role in the gentamicin-induced pathological changes of cochlear IHC ribbon synaptic elements. In normal mature mouse cochleae, the majority of NMDARs were distributed on the modiolar side of IHCs and close to the IHC nuclei region, while most of synaptic ribbons and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) were located on neural terminals closer to the IHC basal poles. After gentamicin exposure, the NMDARs increased and moved towards the IHC basal poles. At the same time, synaptic ribbons and AMPARs moved toward the IHC bundle poles on the afferent dendrites. The number of ribbon synapse decreased, and this was accompanied by increased auditory brainstem response thresholds and reduced wave I amplitudes. NMDAR antagonist MK801 treatment reduced the gentamicin-induced hearing loss and the pathological changes of IHC ribbon synapse, suggesting that NMDARs were involved in gentamicin-induced ototoxicity by regulating the number and distribution of IHC ribbon synapses.

scholarly journals Age-related decline in behavioral discrimination of amplitude modulation frequencies compared to envelope-following responses

2017 ◽  
Author(s):  
Jesyin Lai ◽  
Edward L. Bartlett
Keyword(s):  
Amplitude Modulation ◽  
Speech Intelligibility ◽  
Modulation Depth ◽  
Acoustic Startle ◽  
Hearing Threshold ◽  
Auditory Brainstem ◽  
Acoustic Startle Reflex ◽  
Neural Activation ◽  
Age Related ◽  
Brainstem Response

AbstractThe ability to discriminate modulation frequencies is important for speech intelligibility because speech has amplitude and frequency modulations. Neurophysiological responses assessed by envelope following responses (EFRs) significantly decline at faster amplitude modulation frequencies (AMF) in older subjects. A typical assumption is that a decline in EFRs will necessarily result in corresponding perceptual deficits. To test this assumption, we investigated young and aged Fischer-344 rats’ behavioral AMF discrimination abilities and compared to their EFRs. A modified version of prepulse inhibition (PPI) of acoustic startle reflex (ASR) was used to obtain behavioral performance. A PPI trial contains pulses of sinusoidal AM (SAM) at 128 Hz presented sequentially, a SAM prepulse with different AMF and a startle-eliciting-stimulus. To account for hearing threshold shift or age-related synaptopathy, stimulus levels were presented at 10-dB lower or match to the aged peripheral neural activation (using auditory brainstem response wave I amplitude). When AMF differences and modulation depths were large, young and aged animals’ behavioral performances were comparable. Aged animals’ AMF discrimination abilities declined as the AMF difference or the modulation depth reduced, even compared to the young with peripheral matching. Young animals showed smaller relative decreases in EFRs with reduced modulation depths. The correlation of EFRs and AM perception was identified to be more consistent in young animals. The overall results revealed larger age-related deficits in behavioral perception compared to EFRs, suggesting additional factors that affect perception despite smaller degradation in neural responses. Hence, behavioral and physiological measurements are critical in unveiling a more complete picture on the auditory function.

scholarly journals Hyperexcitability of inferior colliculus and acoustic startle reflex with age-related hearing loss

2017 ◽  
Vol 350 ◽  
pp. 32-42 ◽  
Author(s):  
Binbin Xiong ◽  
Ana'am Alkharabsheh ◽  
Senthilvelan Manohar ◽  
Guang-Di Chen ◽  
Ning Yu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inferior Colliculus ◽  
Acoustic Startle ◽  
Startle Reflex ◽  
Acoustic Startle Reflex ◽  
Age Related ◽  
Age Related Hearing Loss

scholarly journals Chronic Oral Selegiline Treatment Mitigates Age-Related Hearing Loss in BALB/c Mice

2021 ◽  
Vol 22 (6) ◽  
pp. 2853
Author(s):  
Judit Szepesy ◽  
Viktória Humli ◽  
János Farkas ◽  
Ildikó Miklya ◽  
Júlia Tímár ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hearing Aids ◽  
Dose Range ◽  
Auditory Brainstem ◽  
High Frequency Hearing Loss ◽  
Age Related ◽  
Hearing Function ◽  
Brainstem Response ◽  
Aging Societies ◽  
Age Related Hearing Loss

Age-related hearing loss (ARHL), a sensorineural hearing loss of multifactorial origin, increases its prevalence in aging societies. Besides hearing aids and cochlear implants, there is no FDA approved efficient pharmacotherapy to either cure or prevent ARHL. We hypothesized that selegiline, an antiparkinsonian drug, could be a promising candidate for the treatment due to its complex neuroprotective, antioxidant, antiapoptotic, and dopaminergic neurotransmission enhancing effects. We monitored by repeated Auditory Brainstem Response (ABR) measurements the effect of chronic per os selegiline administration on the hearing function in BALB/c and DBA/2J mice, which strains exhibit moderate and rapid progressive high frequency hearing loss, respectively. The treatments were started at 1 month of age and lasted until almost a year and 5 months of age, respectively. In BALB/c mice, 4 mg/kg selegiline significantly mitigated the progression of ARHL at higher frequencies. Used in a wide dose range (0.15–45 mg/kg), selegiline had no effect in DBA/2J mice. Our results suggest that selegiline can partially preserve the hearing in certain forms of ARHL by alleviating its development. It might also be otoprotective in other mammals or humans.

scholarly journals Auditory brainstem gap responses start to decline in mice in middle age: a novel physiological biomarker for age-related hearing loss

2014 ◽  
Vol 361 (1) ◽  
pp. 359-369 ◽  
Author(s):  
Tanika T. Williamson ◽  
Xiaoxia Zhu ◽  
Joseph P. Walton ◽  
Robert D. Frisina
Keyword(s):  
Hearing Loss ◽  
Middle Age ◽  
Auditory Brainstem ◽  
Age Related ◽  
Age Related Hearing Loss

scholarly journals Deletion of Oncomodulin Gives Rise to Early Progressive Cochlear Dysfunction in C57 and CBA Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Leslie K. Climer ◽  
Aubrey J. Hornak ◽  
Kaitlin Murtha ◽  
Yang Yang ◽  
Andrew M. Cox ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Cell Function ◽  
Otoacoustic Emission ◽  
Cell Types ◽  
Auditory Brainstem ◽  
Outer Hair Cells ◽  
Distortion Product Otoacoustic Emission ◽  
Distortion Product ◽  
Age Related ◽  
Brainstem Response

Ca2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca2+ binding protein (CaBP) preferentially expressed in outer hair cells (OHCs) of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM delays 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 age-related hearing loss (ARHL) of the Ocm KO illustrates the importance of Ca2+ signaling in maintaining hearing health. Manipulation of OCM and Ca2+ signaling may reveal important clues to the systems of function/dysfunction that lead to ARHL.

scholarly journals Inner hair cell dysfunction in Klhl18 mutant mice leads to low frequency progressive hearing loss

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258158
Author(s):  
Neil J. Ingham ◽  
Navid Banafshe ◽  
Clarisse Panganiban ◽  
Julia L. Crunden ◽  
Jing Chen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Cell Function ◽  
Low Frequency ◽  
Mutant Mice ◽  
Auditory Brainstem Responses ◽  
Distortion Product Otoacoustic Emission ◽  
Inner Hair Cell ◽  
Distortion Product ◽  
Age Related

Age-related hearing loss in humans (presbycusis) typically involves impairment of high frequency sensitivity before becoming progressively more severe at lower frequencies. Pathologies initially affecting lower frequency regions of hearing are less common. Here we describe a progressive, predominantly low-frequency recessive hearing impairment in two mutant mouse lines carrying different mutant alleles of the Klhl18 gene: a spontaneous missense mutation (Klhl18lowf) and a targeted mutation (Klhl18tm1a(KOMP)Wtsi). Both males and females were studied, and the two mutant lines showed similar phenotypes. Threshold for auditory brainstem responses (ABR; a measure of auditory nerve and brainstem neural activity) were normal at 3 weeks old but showed progressive increases from 4 weeks onwards. In contrast, distortion product otoacoustic emission (DPOAE) sensitivity and amplitudes (a reflection of cochlear outer hair cell function) remained normal in mutants. Electrophysiological recordings from the round window of Klhl18lowf mutants at 6 weeks old revealed 1) raised compound action potential thresholds that were similar to ABR thresholds, 2) cochlear microphonic potentials that were normal compared with wildtype and heterozygous control mice and 3) summating potentials that were reduced in amplitude compared to control mice. Scanning electron microscopy showed that Klhl18lowf mutant mice had abnormally tapering of the tips of inner hair cell stereocilia in the apical half of the cochlea while their synapses appeared normal. These results suggest that Klhl18 is necessary to maintain inner hair cell stereocilia and normal inner hair cell function at low frequencies.

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