Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

Seist, Richard; Tong, Mingjie; Landegger, Lukas D.; Vasilijić, Saša; Hyakusoku, Hiroshi; Katsumi, Sachiyo; McKenna, Charles E.; Stanković, Konstantina M.

doi:10.3389/fnmol.2020.00087

Cited by 25 publications

(25 citation statements)

References 54 publications

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“…Because of the type 1C response, reversal of cochlear synaptopathy following noise has been a topic of intense research (Fernandez et al, 2021a;Hashimoto et al, 2019;Seist et al, 2020). A recently published study showed that treatment of mice with zoledronic acid after TTS-inducing noise can reverse synaptopathy, likely via the inhibition of the Farnesyl pyrophosphate synthase (FDPS) enzyme (Seist et al, 2020). Our study shows that expression of Fdps in the spiral ganglion is primarily limited to Schwann cells and type 2 SGNs, with a significant decrease in expression in Schwann cells following noise.…”

Section: Discussionmentioning

confidence: 99%

A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma

Milon

Shulman

et al. 2021

Cell Reports

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Section: Discussionmentioning

confidence: 99%

A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma

Milon

Shulman

et al. 2021

Cell Reports

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“…The observed protection from synaptopathy may occur via prevention of the uncoupling of the paired IHC-ANF synapses, synaptic regeneration, or a combination of both phenomena. Recent studies demonstrate the potential for synaptic regeneration as treatment with bisphosphonates 24-h post-exposure can reverse synaptopathy [42]. Histological evaluation at additional post-exposure timepoints is needed to discriminate the two proposed mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Estradiol Protects against Noise-Induced Hearing Loss and Modulates Auditory Physiology in Female Mice

Shuster

Casserly

Lipford

et al. 2021

IJMS

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Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17β-estradiol (E2), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)- and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL.

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“…ABRs and DPOAEs were recorded as detailed previously ( Seist et al, 2020 ). Briefly, mice were anesthetized with intraperitoneally administered ketamine (100 mg/kg) and xylazine (10 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

Cochlin Deficiency Protects Against Noise-Induced Hearing Loss

Seist

Landegger

Robertson

et al. 2021

Front. Mol. Neurosci.

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Cochlin is the most abundant protein in the inner ear. To study its function in response to noise trauma, we exposed adolescent wild-type (Coch+/+) and cochlin knock-out (Coch–/–) mice to noise (8–16 kHz, 103 dB SPL, 2 h) that causes a permanent threshold shift and hair cell loss. Two weeks after noise exposure, Coch–/– mice had substantially less elevation in noise-induced auditory thresholds and hair cell loss than Coch+/+ mice, consistent with cochlin deficiency providing protection from noise trauma. Comparison of pre-noise exposure thresholds of auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) in Coch–/– mice and Coch+/+ littermates revealed a small and significant elevation in thresholds of Coch–/– mice, overall consistent with a small conductive hearing loss in Coch–/– mice. We show quantitatively that the pro-inflammatory component of cochlin, LCCL, is upregulated after noise exposure in perilymph of wild-type mice compared to unexposed mice, as is the enzyme catalyzing LCCL release, aggrecanase1, encoded by Adamts4. We further show that upregulation of pro-inflammatory cytokines in perilymph and cochlear soft-tissue after noise exposure is lower in cochlin knock-out than wild-type mice. Taken together, our data demonstrate for the first time that cochlin deficiency results in conductive hearing loss that protects against physiologic and molecular effects of noise trauma.

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Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate

Cited by 25 publications

References 54 publications

A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma

A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma

Estradiol Protects against Noise-Induced Hearing Loss and Modulates Auditory Physiology in Female Mice

Cochlin Deficiency Protects Against Noise-Induced Hearing Loss

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