Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice with Targeted Deletion of Slc44a2/Ctl2

The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a “hidden hearing loss” for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

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Rate of Spiral Ganglion Cell Loss in Idiopathic Sudden Sensorineural Hearing Loss

Otology & Neurotology ◽

10.1097/mao.0000000000001992 ◽

2018 ◽

Vol 39 (10) ◽

pp. e944-e949 ◽

Cited By ~ 1

Author(s):

Omer J. Ungar ◽

Ophir Handzel ◽

Felipe Santos

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Ganglion Cell ◽

Spiral Ganglion ◽

Cell Loss ◽

Sudden Sensorineural Hearing Loss ◽

Sensorineural Hearing ◽

Spiral Ganglion Cell

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Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing

Genome Biology ◽

10.1186/s13059-021-02311-4 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Xi Gu ◽

Daqi Wang ◽

Zhijiao Xu ◽

Jinghan Wang ◽

Luo Guo ◽

...

Keyword(s):

Hearing Loss ◽

Protective Effect ◽

Hair Cell ◽

Sensorineural Hearing Loss ◽

Auditory Brainstem Response ◽

Gene Editing ◽

Auditory Brainstem ◽

Sensorineural Hearing ◽

Brainstem Response

Abstract Background Aging, noise, infection, and ototoxic drugs are the major causes of human acquired sensorineural hearing loss, but treatment options are limited. CRISPR/Cas9 technology has tremendous potential to become a new therapeutic modality for acquired non-inherited sensorineural hearing loss. Here, we develop CRISPR/Cas9 strategies to prevent aminoglycoside-induced deafness, a common type of acquired non-inherited sensorineural hearing loss, via disrupting the Htra2 gene in the inner ear which is involved in apoptosis but has not been investigated in cochlear hair cell protection. Results The results indicate that adeno-associated virus (AAV)-mediated delivery of CRISPR/SpCas9 system ameliorates neomycin-induced apoptosis, promotes hair cell survival, and significantly improves hearing function in neomycin-treated mice. The protective effect of the AAV–CRISPR/Cas9 system in vivo is sustained up to 8 weeks after neomycin exposure. For more efficient delivery of the whole CRISPR/Cas9 system, we also explore the AAV–CRISPR/SaCas9 system to prevent neomycin-induced deafness. The in vivo editing efficiency of the SaCas9 system is 1.73% on average. We observed significant improvement in auditory brainstem response thresholds in the injected ears compared with the non-injected ears. At 4 weeks after neomycin exposure, the protective effect of the AAV–CRISPR/SaCas9 system is still obvious, with the improvement in auditory brainstem response threshold up to 50 dB at 8 kHz. Conclusions These findings demonstrate the safe and effective prevention of aminoglycoside-induced deafness via Htra2 gene editing and support further development of the CRISPR/Cas9 technology in the treatment of non-inherited hearing loss as well as other non-inherited diseases.

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MCMV triggers ROS/NLRP3-associated inflammasome activation in the inner ear of mice and cultured spiral ganglion neurons, contributing to sensorineural hearing loss

International Journal of Molecular Medicine ◽

10.3892/ijmm.2018.3539 ◽

2018 ◽

Cited By ~ 5

Author(s):

Wei Zhuang ◽

Caiji Wang ◽

Xi Shi ◽

Shiwei Qiu ◽

Shili Zhang ◽

...

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Inner Ear ◽

Spiral Ganglion ◽

Sensorineural Hearing ◽

Inflammasome Activation ◽

Spiral Ganglion Neurons ◽

Ganglion Neurons

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Using the Zebrafish Lateral Line to Understand the Roles of Mitochondria in Sensorineural Hearing Loss

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.628712 ◽

2021 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

Melanie Holmgren ◽

Lavinia Sheets

Keyword(s):

Cell Death ◽

Hearing Loss ◽

Hair Cell ◽

Sensorineural Hearing Loss ◽

Lateral Line ◽

Hair Cells ◽

High Energy ◽

Sensorineural Hearing ◽

Mitochondrial Activity ◽

Ototoxic Drugs

Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model in which to study hair-cell mitochondrial activity. Moreover, the ease of genetic manipulation of zebrafish embryos allows for the study of mutations implicated in human deafness, as well as the generation of transgenic models to visualize mitochondrial calcium transients and mitochondrial activity in live organisms. Studies of the zebrafish lateral line have shown that variations in mitochondrial activity can predict hair-cell susceptibility to damage by aminoglycosides or noise exposure. In addition, antioxidants have been shown to protect against noise trauma and ototoxic drug–induced hair-cell death. In this review, we discuss the tools and findings of recent investigations into zebrafish hair-cell mitochondria and their involvement in cellular processes, both under homeostatic conditions and in response to noise or ototoxic drugs. The zebrafish lateral line is a valuable model in which to study the roles of mitochondria in hair-cell pathologies and to develop therapeutic strategies to prevent sensorineural hearing loss in humans.

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Neurotrophin gene therapy may be able to treat individuals with noise-induced hearing loss or neural presbyacusis

10.31219/osf.io/spkxh ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Gene Therapy ◽

Hearing Loss ◽

Hair Cell ◽

Hair Cells ◽

Cell Loss ◽

Cell Populations ◽

Noise Induced Hearing Loss ◽

Hair Cell Loss ◽

Functional Impairments ◽

Peripheral Axon

Neurotrophin (NT) cochlear gene therapy might perhaps give a single treatment that might greatly enhance neuronal survival, resulting in CI patients, provided the many challenges described above can be adequately addressed and safety concerns allayed by more animal model investigations. This is particularly crucial for juvenile CI patients, who have to rely on electrical hearing for the remainder of their lives, and whose outcomes are quite different. In addition, NT gene therapy may have the potential to treat patients with noise-induced hearing loss or neural presbyacusis (e.g., age-related cochlear synaptopathy), where primary neuronal loss is a key cause of hearing loss. Animal research into noise-induced hearing loss has shown that even exposures that generate only reversible threshold alterations and no hair cell loss can lead to permanent loss of SGN synapses on hair cells, resulting in functional impairments and ultimately SGN degeneration. Cochlear synapses frequently precede both hair cell loss and threshold increases in human ears, according to current studies. Cochlear synaptopathy is characterized by ears with intact hair cell populations and normal audiograms as "hidden" hearing loss. Many frequent perceptual abnormalities, including speech-in-noise difficulties, tinnitus, and hyperacusis, are likely produced by suppressing affected neurons, which radically alters information processing. Thus, in the future, NT gene therapy may be successful in inducing SGN peripheral axon resprouting and synaptic regeneration into residual (or even regenerated) hair cell populations. We have demonstrated compelling evidence that, in this investigation, BDNF gene therapy can boost SGN survival and enhance peripheral axon maintenance or rerouting. NT-3 has been found in adult animals exposed to acoustic damage to induce synaptic regeneration of these fibers, reconnecting them to hair cells and their ribbon synapses, and restoring hearing function. Combining BDNF and NT-3 gene therapy may be the most effective way to maintain/restore a more normal cochlear neuronal substrate.

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Mechanisms of hearing loss and cell death in the cochlea of connexin mutant mice

AJP Cell Physiology ◽

10.1152/ajpcell.00483.2019 ◽

2020 ◽

Vol 319 (3) ◽

pp. C569-C578

Author(s):

Bei Chen ◽

Hongen Xu ◽

Yanfang Mi ◽

Wei Jiang ◽

Dan Guo ◽

...

Keyword(s):

Oxidative Stress ◽

Hearing Loss ◽

Hair Cell ◽

Stria Vascularis ◽

Reactive Oxygen Species Generation ◽

Cell Loss ◽

Outer Hair Cells ◽

Spiral Ligament ◽

Hair Cell Loss ◽

Auditory Brain Stem Response

Mutations in connexin 30 (Cx30) are known to cause severe congenital hearing impairment; however, the mechanism by which Cx30 mediates homeostasis of endocochlear gap junctions is unclear. We used a gene deletion mouse model to explore the mechanisms of Cx30 in preventing hearing loss. Our results suggest that despite severe loss of the auditory brain-stem response and endocochlear potential at postnatal day 18, Cx30−/− mice only show sporadic loss of the outer hair cells. This inconsistency in the time course and severity of hearing and hair cell losses in Cx30−/− mice might be explained, in part, by an increase in reactive oxygen species generation beginning at postnatal day 10. The expression of oxidative stress genes was increased in Cx30−/− mice in the stria vascularis, spiral ligament, and organ of Corti. Furthermore, Cx30 deficiency caused mitochondrial dysfunction at postnatal day 18, as assessed by decreased ATP levels and decreased expression of mitochondrial complex I proteins, especially in the stria vascularis. Proteomic analysis further identified 444 proteins that were dysregulated in Cx30−/− mice, including several that are involved in mitochondria electron transport, ATP synthesis, or ion transport. Additionally, proapoptotic proteins, including Bax, Bad, and caspase-3, were upregulated at postnatal day 18, providing a molecular basis to explain the loss of hearing that occurs before hair cell loss. Therefore, our results are consistent with an environment of oxidative stress and mitochondrial damage in the cochlea of Cx30−/− mice that is coincident with hearing loss but precedes hair cell loss.

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