scholarly journals Physiopathological Relevance of D-Serine in the Mammalian Cochlea

2021 ◽  
Vol 15 ◽  
Author(s):  
Jing Wang ◽  
Nicolas Serratrice ◽  
Cindy J. Lee ◽  
Florence François ◽  
Jonathan V. Sweedler ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Nmda Receptors ◽  
Guinea Pigs ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Nerve Fibers ◽  
Inner Hair Cell ◽  
Ganglion Neurons

NMDA receptors (NMDARs) populate the complex between inner hair cell (IHC) and spiral ganglion neurons (SGNs) in the developing and mature cochlea. However, in the mature cochlea, activation of NMDARs is thought to mainly occur under pathological conditions such as excitotoxicity. Ototoxic drugs such as aspirin enable cochlear arachidonic-acid-sensitive NMDAR responses, and induced chronic tinnitus was blocked by local application of NMDAR antagonists into the cochlear fluids. We largely ignore if other modulators are also engaged. In the brain, D-serine is the primary physiological co-agonist of synaptic NMDARs. Whether D-serine plays a role in the cochlea had remained unexplored. We now reveal the presence of D-serine and its metabolic enzymes prior to, and at hearing onset, in the sensory and non-neuronal cells of the cochlea of several vertebrate species. In vivo intracochlear perfusion of D-serine in guinea pigs reduces sound-evoked activity of auditory nerve fibers without affecting the receptor potentials, suggesting that D-serine acts specifically on the postsynaptic auditory neurons without altering the functional state of IHC or of the stria vascularis. Indeed, we demonstrate in vitro that agonist-induced activation of NMDARs produces robust calcium responses in rat SGN somata only in the presence of D-serine, but not of glycine. Surprisingly, genetic deletion in mice of serine racemase (SR), the enzyme that catalyzes D-serine, does not affect hearing function, but offers protection against noise-induced permanent hearing loss as measured 3 months after exposure. However, the mechanisms of activation of NMDA receptors in newborn rats may be different from those in adult guinea pigs. Taken together, these results demonstrate for the first time that the neuro-messenger D-serine has a pivotal role in the cochlea by promoting the activation of silent cochlear NMDAR in pathological situations. Thus, D-serine and its signaling pathway may represent a new druggable target for treating sensorineural hearing disorders (i.e., hearing loss, tinnitus).

scholarly journals Spatiotemporal Developmental Upregulation of Prestin Correlates With the Severity and Location of Cyclodextrin-Induced Outer Hair Cell Loss and Hearing Loss

2021 ◽  
Vol 9 ◽  
Author(s):  
Dalian Ding ◽  
Haiyan Jiang ◽  
Senthilvelan Manohar ◽  
Xiaopeng Liu ◽  
Li Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Auditory Nerve ◽  
High Frequency ◽  
Spiral Ganglion ◽  
Low Frequency ◽  
Nerve Fibers ◽  
Spiral Ganglion Neurons ◽  
Auditory Nerve Fibers ◽  
Ganglion Neurons

2-Hyroxypropyl-beta-cyclodextrin (HPβCD) is being used to treat Niemann-Pick C1, a fatal neurodegenerative disease caused by abnormal cholesterol metabolism. HPβCD slows disease progression, but unfortunately causes severe, rapid onset hearing loss by destroying the outer hair cells (OHC). HPβCD-induced damage is believed to be related to the expression of prestin in OHCs. Because prestin is postnatally upregulated from the cochlear base toward the apex, we hypothesized that HPβCD ototoxicity would spread from the high-frequency base toward the low-frequency apex of the cochlea. Consistent with this hypothesis, cochlear hearing impairments and OHC loss rapidly spread from the high-frequency base toward the low-frequency apex of the cochlea when HPβCD administration shifted from postnatal day 3 (P3) to P28. HPβCD-induced histopathologies were initially confined to the OHCs, but between 4- and 6-weeks post-treatment, there was an unexpected, rapid and massive expansion of the lesion to include most inner hair cells (IHC), pillar cells (PC), peripheral auditory nerve fibers, and spiral ganglion neurons at location where OHCs were missing. The magnitude and spatial extent of HPβCD-induced OHC death was tightly correlated with the postnatal day when HPβCD was administered which coincided with the spatiotemporal upregulation of prestin in OHCs. A second, massive wave of degeneration involving IHCs, PC, auditory nerve fibers and spiral ganglion neurons abruptly emerged 4–6 weeks post-HPβCD treatment. This secondary wave of degeneration combined with the initial OHC loss results in a profound, irreversible hearing loss.

scholarly journals Caffeine Induces Autophagy and Apoptosis in Auditory Hair Cells via the SGK1/HIF-1α Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaomin Tang ◽  
Yuxuan Sun ◽  
Chenyu Xu ◽  
Xiaotao Guo ◽  
Jiaqiang Sun ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Spiral Ganglion Neurons ◽  
Auditory Hair Cells ◽  
Qrt Pcr ◽  
Ganglion Neurons

Caffeine is being increasingly used in daily life, such as in drinks, cosmetics, and medicine. Caffeine is known as a mild stimulant of the central nervous system, which is also closely related to neurologic disease. However, it is unknown whether caffeine causes hearing loss, and there is great interest in determining the effect of caffeine in cochlear hair cells. First, we explored the difference in auditory brainstem response (ABR), organ of Corti, stria vascularis, and spiral ganglion neurons between the control and caffeine-treated groups of C57BL/6 mice. RNA sequencing was conducted to profile mRNA expression differences in the cochlea of control and caffeine-treated mice. A CCK-8 assay was used to evaluate the approximate concentration of caffeine. Flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting were performed to detect the effects of SGK1 in HEI-OC1 cells and basilar membranes. In vivo research showed that 120 mg/ kg caffeine injection caused hearing loss by damaging the organ of Corti, stria vascularis, and spiral ganglion neurons. RNA-seq results suggested that SGK1 might play a vital role in ototoxicity. To confirm our observations in vitro, we used the HEI-OC1 cell line, a cochlear hair cell-like cell line, to investigate the role of caffeine in hearing loss. The results of flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting showed that caffeine caused autophagy and apoptosis via SGK1 pathway. We verified the interaction between SGK1 and HIF-1α by co-IP. To confirm the role of SGK1 and HIF-1α, GSK650394 was used as an inhibitor of SGK1 and CoCl2 was used as an inducer of HIF-1α. Western blot analysis suggested that GSK650394 and CoCl2 relieved the caffeine-induced apoptosis and autophagy. Together, these results indicated that caffeine induces autophagy and apoptosis in auditory hair cells via the SGK1/HIF-1α pathway, suggesting that caffeine may cause hearing loss. Additionally, our findings provided new insights into ototoxic drugs, demonstrating that SGK1 and its downstream pathways may be potential therapeutic targets for hearing research at the molecular level.

Cochlear Dead Regions in Sporadic Unilateral Vestibular Schwannomas Using the Threshold-Equalizing Noise Test

2019 ◽  
Vol 24 (6) ◽  
pp. 271-278
Author(s):  
Hayoung Byun ◽  
Yang-Sun Cho ◽  
Sung Hwa Hong ◽  
Il Joon Moon
Keyword(s):  
Hearing Loss ◽  
Pure Tone ◽  
Spiral Ganglion ◽  
Tumor Location ◽  
Common Symptom ◽  
Low Frequencies ◽  
Hearing Thresholds ◽  
Ganglion Neurons ◽  
Cochlear Dead Regions

Background: Vestibular schwannoma (VS) is a benign intracranial neoplasm originating in the Schwann cells of the vestibular nerve. Despite its origin, the most common symptom is sensorineural hearing loss which is presented in more than 90% of patients. The underlying pathophysiology of this hearing loss has not been fully understood. Objective: To assess the in vivo function of cochlear inner hair cells and spiral ganglion neurons in VS, cochlear dead regions (DRs) were evaluated via the threshold-equalizing noise (TEN) test in untreated VS patients. Method: Untreated patients diagnosed with sporadic unilateral VS and normal contralesional hearing were enrolled from July 2011 to June 2016. Audiometric evaluation including TEN tests were performed. Based on the magnetic resonance findings, characteristics of individual tumors were assessed. Results: The average pure-tone threshold (word recognition score [WRS]) of 23 enrolled patients was 42.7 dB (76.1%). Nineteen DRs (11.8% of 161 tested frequencies) were found in 8 patients (34.8% of enrolled cases). Among the intracanalicular (IAC) tumors, 6 out of 10 ears (60%) carried DRs, while 2 of 13 (15.4%) showed DRs among the cerebellopontine angle (CPA) lesions (p = 0.039). Pure-tone thresholds and WRS were not different between the two groups. Logistic regression analysis showed that the tumor location, IAC versus CPA, was significantly associated with DRs (p = 0.041, Nagelkerke R2 = 0.471), whereas age, sex, tumor size, distance from the tumor to the cochlea, T2-weighted hypointensity on the MRI and pure-tone thresholds showed no significance. Conclusions: Cochlear DRs are detected in hearing losses associated with unilateral sporadic VS using the TEN test. Individual DRs were detected variously in high, mid, or low frequencies. In our preliminary data, IAC tumors showed a higher number of DRs than CPA tumors despite similar average hearing thresholds. Further studies including longitudinal follow-up of hearing as well as change in DRs may provide useful information about VS patients.

scholarly journals Association of the Kv1 family of K+ channels and their functional blueprint in the properties of auditory neurons as revealed by genetic and functional analyses

2013 ◽  
Vol 110 (8) ◽  
pp. 1751-1764 ◽  
Author(s):  
Wenying Wang ◽  
Hyo Jeong Kim ◽  
Ping Lv ◽  
Bruce Tempel ◽  
Ebenezer N. Yamoah
Keyword(s):  
Membrane Potential ◽  
Developmental Plasticity ◽  
Spiral Ganglion ◽  
Membrane Properties ◽  
Resting Membrane Potential ◽  
Underlying Mechanisms ◽  
Null Mutant Mice ◽  
Ganglion Neurons

Developmental plasticity in spiral ganglion neurons (SGNs) ensues from profound alterations in the functional properties of the developing hair cell (HC). For example, prehearing HCs are spontaneously active. However, at the posthearing stage, HC membrane properties transition to graded receptor potentials. The dendrotoxin (DTX)-sensitive Kv1 channel subunits (Kv1.1, 1.2, and 1.6) shape the firing properties and membrane potential of SGNs, and the expression of the channel undergoes developmental changes. Because of the stochastic nature of Kv subunit heteromultimerization, it has been difficult to determine physiologically relevant subunit-specific interactions and their functions in the underlying mechanisms of Kv1 channel plasticity in SGNs. Using Kcna2 null mutant mice, we demonstrate a surprising paradox in changes in the membrane properties of SGNs. The resting membrane potential of Kcna2−/− SGNs was significantly hyperpolarized compared with that of age-matched wild-type (WT) SGNs. Analyses of outward currents in the mutant SGNs suggest an apparent approximately twofold increase in outward K+ currents. We show that in vivo and in vitro heteromultimerization of Kv1.2 and Kv1.4 α-subunits underlies the striking and unexpected alterations in the properties of SGNs. The results suggest that heteromeric interactions of Kv1.2 and Kv1.4 dominate the defining features of Kv1 channels in SGNs.

scholarly journals Oxidative Stresses and Mitochondrial Dysfunction in Age-Related Hearing Loss

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Chisato Fujimoto ◽  
Tatsuya Yamasoba
Keyword(s):  
Hearing Loss ◽  
Mitochondrial Dysfunction ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
The Elderly ◽  
Laboratory Animals ◽  
Age Related ◽  
Ganglion Neurons ◽  
Age Related Hearing Loss

Age-related hearing loss (ARHL), the progressive loss of hearing associated with aging, is the most common sensory disorder in the elderly population. The pathology of ARHL includes the hair cells of the organ of Corti, stria vascularis, and afferent spiral ganglion neurons as well as the central auditory pathways. Many studies have suggested that the accumulation of mitochondrial DNA damage, the production of reactive oxygen species, and decreased antioxidant function are associated with subsequent cochlear senescence in response to aging stress. Mitochondria play a crucial role in the induction of intrinsic apoptosis in cochlear cells. ARHL can be prevented in laboratory animals by certain interventions, such as caloric restriction and supplementation with antioxidants. In this review, we will focus on previous research concerning the role of the oxidative stress and mitochondrial dysfunction in the pathology of ARHL in both animal models and humans and introduce concepts that have recently emerged regarding the mechanisms of the development of ARHL.

scholarly journals EFFECTS OF THALLIUM SALTS ON NEURONAL MITOCHONDRIA IN ORGANOTYPIC CORD-GANGLIA-MUSCLE COMBINATION CULTURES

1973 ◽  
Vol 58 (1) ◽  
pp. 79-95 ◽  
Author(s):  
Peter S. Spencer ◽  
Edith R. Peterson ◽  
Ricardo Madrid A. ◽  
Cedric S. Raine
Keyword(s):  
Peripheral Nerve ◽  
Dorsal Root ◽  
Time Course ◽  
Nerve Fibers ◽  
Dorsal Root Ganglion Neurons ◽  
Matrix Space ◽  
Neurotoxic Effects ◽  
Ganglion Neurons

A functionally coupled organotypic complex of cultured dorsal root ganglia, spinal cord peripheral nerve, and muscle has been employed in an experimental approach to the investigation of the neurotoxic effects of thallium. Selected cultures, grown for up to 12 wk in vitro, were exposed to thallous salts for periods ranging up to 4 days. Cytopathic effects were first detected after 2 h of exposure with the appearance of considerably enlarged mitochondria in axons of peripheral nerve fibers. With time, the matrix space of these mitochondria became progressively swollen, transforming the organelle into an axonal vacuole bounded by the original outer mitochondrial membrane. Coalescence of adjacent axonal vacuoles produced massive internal axon compartments, the membranes of which were shown by electron microprobe mass spectrometry to have an affinity for thallium. Other axoplasmic components were displaced within a distended but intact axolemma. The resultant fiber swelling caused myelin retraction from nodes of Ranvier but no degeneration. Impulses could still propagate along the nerve fibers throughout the time course of the experiment. Comparable, but less severe changes were seen in dorsal root ganglion neurons and in central nerve fibers. Other cell types showed no mitochondrial change. It is uncertain how these findings relate to the neurotoxic effects of thallium in vivo, but a sensitivity of the nerve cell and especially its axon to thallous salts is indicated.

scholarly journals Cisplatin-Induced Ototoxicity in Rats Is Driven by RIP3-Dependent Necroptosis

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 409 ◽  
Author(s):  
Mi-Jin Choi ◽  
Hyunsook Kang ◽  
Yun Yeong Lee ◽  
Oak-Sung Choo ◽  
Jeong Hun Jang ◽  
...  
Keyword(s):  
Cell Death ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Auditory Brainstem ◽  
Sprague Dawley ◽  
Western Blots ◽  
Brainstem Response ◽  
Ganglion Neurons

Cisplatin-induced early-onset ototoxicity is linked to hearing loss. The mechanism by which cisplatin causes ototoxicity remains unclear. The purpose of this study was to identify the involvement of receptor-interacting protein kinase (RIP)3-dependent necroptosis in cisplatin-induced ototoxicity in vitro and in vivo. Sprague–Dawley rats (SD, 8 week) were treated via intraperitoneal (i.p.) injection with cisplatin (16 mg/kg for 1 day), and their hearing thresholds were measured by the auditory brainstem response (ABR) method. Hematoxylin and eosin (H & E) staining, immunohistochemistry, and western blots were performed to determine the effect of cisplatin-induced ototoxicity on cochlear morphology. Inhibitor experiments with necrostatin 1 (Nec-1) and Z-VAD were also performed in HEI-OC1 cell line. H&E stains revealed that the necroptotic changes were increased in the organ of Corti (OC) and spiral ganglion neurons (SGNs). Moreover, immunohistochemistry and western blot analysis showed that cisplatin treatment increased the protein levels of RIP3 in both OCs and SGNs. The treatment of Nec-1, a selective RIP1 inhibitor, resulted in markedly suppression of cisplatin-induced cell death in HEI-OC1 cells, whereas Z-VAD treatment did not change the cisplatin-induced cell death. Our results suggest that RIP3-dependent necroptosis was substantial in cisplatin-induced ototoxicity; inner cochlear regions, the OCs, and SGNs were especially sensitive to necroptosis.

scholarly journals Cochlear Synaptopathy and Noise-Induced Hidden Hearing Loss

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Lijuan Shi ◽  
Ying Chang ◽  
Xiaowei Li ◽  
Steve Aiken ◽  
Lijie Liu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Noise Exposure ◽  
Human Subjects ◽  
Spiral Ganglion ◽  
Nerve Fibers ◽  
Type I ◽  
Functional Deficits ◽  
Ganglion Neurons ◽  
Hidden Hearing Loss ◽  
Signal Coding

Recent studies on animal models have shown that noise exposure that does not lead to permanent threshold shift (PTS) can cause considerable damage around the synapses between inner hair cells (IHCs) and type-I afferent auditory nerve fibers (ANFs). Disruption of these synapses not only disables the innervated ANFs but also results in the slow degeneration of spiral ganglion neurons if the synapses are not reestablished. Such a loss of ANFs should result in signal coding deficits, which are exacerbated by the bias of the damage toward synapses connecting low-spontaneous-rate (SR) ANFs, which are known to be vital for signal coding in noisy background. As there is no PTS, these functional deficits cannot be detected using routine audiological evaluations and may be unknown to subjects who have them. Such functional deficits in hearing without changes in sensitivity are generally called “noise-induced hidden hearing loss (NIHHL).” Here, we provide a brief review to address several critical issues related to NIHHL: (1) the mechanism of noise induced synaptic damage, (2) reversibility of the synaptic damage, (3) the functional deficits as the nature of NIHHL in animal studies, (4) evidence of NIHHL in human subjects, and (5) peripheral and central contribution of NIHHL.

Artemin improves survival of spiral ganglion neurons in vivo and in vitro

Neuroreport ◽  
2010 ◽  
Vol 21 (7) ◽  
pp. 517-521 ◽  
Author(s):  
Athanasia Warnecke ◽  
Verena Scheper ◽  
Ines Buhr ◽  
Gentiana I. Wenzel ◽  
Kirsten Wissel ◽  
...  
Keyword(s):  
Spiral Ganglion ◽  
Spiral Ganglion Neurons ◽  
Ganglion Neurons

scholarly journals Exacerbated age-related hearing loss in mice lacking the p43 mitochondrial T3 receptor

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Corentin Affortit ◽  
François Casas ◽  
Sabine Ladrech ◽  
Jean-Charles Ceccato ◽  
Jérôme Bourien ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Spiral Ganglion ◽  
Electrophysiological Recording ◽  
Mitochondrial Activity ◽  
P53 Expression ◽  
Age Related ◽  
Hearing Function ◽  
Ganglion Neurons ◽  
Age Related Hearing Loss

Abstract Background Age-related hearing loss (ARHL), also known as presbycusis, is the most common sensory impairment seen in elderly people. However, the cochlear aging process does not affect people uniformly, suggesting that both genetic and environmental (e.g., noise, ototoxic drugs) factors and their interaction may influence the onset and severity of ARHL. Considering the potential links between thyroid hormone, mitochondrial activity, and hearing, here, we probed the role of p43, a N-terminally truncated and ligand-binding form of the nuclear receptor TRα1, in hearing function and in the maintenance of hearing during aging in p43−/− mice through complementary approaches, including in vivo electrophysiological recording, ultrastructural assessments, biochemistry, and molecular biology. Results We found that the p43−/− mice exhibit no obvious hearing loss in juvenile stages, but that these mice developed a premature, and more severe, ARHL resulting from the loss of cochlear sensory outer and inner hair cells and degeneration of spiral ganglion neurons. Exacerbated ARHL in p43−/− mice was associated with the early occurrence of a drastic fall of SIRT1 expression, together with an imbalance between pro-apoptotic Bax, p53 expression, and anti-apoptotic Bcl2 expression, as well as an increase in mitochondrial dysfunction, oxidative stress, and inflammatory process. Finally, p43−/− mice were also more vulnerable to noise-induced hearing loss. Conclusions These results demonstrate for the first time a requirement for p43 in the maintenance of hearing during aging and highlight the need to probe the potential link between human THRA gene polymorphisms and/or mutations and accelerated age-related deafness or some adult-onset syndromic deafness.

Sign in / Sign up

Export Citation Format

Share Document