Spontaneous and Partial Repair of Ribbon Synapse in Cochlear Inner Hair Cells After Ototoxic Withdrawal

Liu, Ke; Chen, Daishi; Guo, Weiwei; Yu, Ning; Wang, Xiao Yu; Ji, Fei; Hou, Zeng-Guang; Wei, Yang; Yang, Shiming

doi:10.1007/s12035-014-8951-y

Cited by 23 publications

(30 citation statements)

References 55 publications

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“…Although partial recovery of auditory function after kanamycin treatment has been described previously, it only occured in regions with lower threshold shifts and greater OHC survival (82). The basis for this partial recovery is thought to be drug clearance from cochlear tissues, facilitating the repair of hair cell and strial physiology incurred during sub-lethal toxicity to resume optimal auditory function (25, 82, 84). However, once threshold shifts exceed >40 dB (akin to the LPS+kanamycin group), no functional or anatomical recovery of hair cells occurred, resulting in a PTS (82, 85).…”

Section: Discussionmentioning

confidence: 99%

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Koo

Quintanilla‐Dieck²,

Jiang³

et al. 2015

Sci. Transl. Med.

130

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The ototoxic aminoglycoside antibiotics are essential to treat severe bacterial infections, particularly in neonatal intensive care units. Using a bacterial lipopolysaccharide (LPS) experimental model of sepsis, we tested whether LPS-mediated inflammation potentiates cochlear uptake of aminoglycosides and permanent hearing loss in mice. Using confocal microscopy and enzyme-linked immunosorbent assays, we found that low-dose LPS (endotoxemia) greatly increased cochlear concentrations of aminoglycosides and resulted in vasodilation of cochlear capillaries without inducing paracellular flux across the blood-labyrinth barrier (BLB), or elevating serum concentrations of the drug. Additionally, endotoxemia increased expression of both serum and cochlear inflammatory markers. These LPS-induced changes, classically mediated by Toll-like Receptor 4 (TLR4), were attenuated in TLR4-hyporesponsive mice. Multiday dosing with aminoglycosides during chronic endotoxemia induced greater hearing threshold shifts and sensory cell loss compared to mice without endotoxemia. Thus, endotoxemia-mediated inflammation enhanced aminoglycoside trafficking across the BLB, and potentiated aminoglycoside-induced ototoxicity. These data indicate that patients with severe infections are at greater risk of aminoglycoside-induced hearing loss than previously recognized.

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Section: Discussionmentioning

confidence: 99%

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Koo

Quintanilla‐Dieck²,

Jiang³

et al. 2015

Sci. Transl. Med.

130

View full text Add to dashboard Cite

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“…Noise-induced synaptic loss is generally believed to be permanent; however, a few reports have suggested that synaptic loss may be partially reversible at early time points post-insult (Shi et al, 2013; Liu et al, 2015). Nonetheless, even in these models, synaptic counts are consistently reduced weeks after noise exposure, reinforcing the long-term irreversibility of synaptic loss without therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Translational issues in cochlear synaptopathy

et al. 2017

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Understanding the biology of the previously underappreciated sensitivity of cochlear synapses to noise insult, and its clinical consequences, is becoming a mission for a growing number of auditory researchers. In addition, several research groups have become interested in developing therapeutic approaches that can reverse synaptopathy and restore hearing function. One of the major challenges to realizing the potential of synaptopathy rodent models is that current clinical audiometric approaches cannot yet reveal the presence of this subtle cochlear pathology in humans. This has catalyzed efforts, both from basic and clinical perspectives, to investigate novel means for diagnosing synaptopathy and to determine the main functional consequences for auditory perception and hearing abilities. Such means, and a strong concordance between findings in pre-clinical animal models and clinical studies in humans, are important for developing and realizing therapeutics. This paper frames the key outstanding translational questions that need to be addressed to realize this ambitious goal.

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“…Liberman et al reported the reorganization of synaptic ribbon locations, the loss of synaptic ribbons, and the downregulation of AMPAR expression in the peripheral terminals after noise exposure [ 7 ]. Liu et al found that moderate ototoxicity in mice leads to reduced numbers and morphologic changes in the synaptic ribbons, which are accompanied by mild hearing loss but no significant loss of HCs or SGNs in the cochlea [ 8 ]. However, the mechanism behind these pathological changes in cochlear IHC ribbon synapse remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Spontaneous and Partial Repair of Ribbon Synapse in Cochlear Inner Hair Cells After Ototoxic Withdrawal

Cited by 23 publications

References 55 publications

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

Translational issues in cochlear synaptopathy

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

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