Degeneration Of Inner Hair Cells Research Articles

Cochlear spiral ganglion neuron degeneration following cyclodextrin-induced hearing loss

Because cyclodextrins are capable of removing cholesterol from cell membranes, there is growing interest in using these compounds to treat diseases linked to aberrant cholesterol metabolism. One compound, 2-hydroxypropyl-beta-cyclodextrin (HPβCD), is currently being evaluated as a treatment for Niemann-Pick Type C1 disease, a rare, fatal neurodegenerative disease caused by the buildup of lipids in endosomes and lysosomes. HPβCD can reduce some debilitating symptoms and extend life span, but the therapeutic doses used to treat the disease cause hearing loss. Initial studies in rodents suggested that HPβCD selectively damaged only cochlear outer hair cells during the first week post-treatment. However, our recent in vivo and in vitro studies suggested that the damage could become progressively worse and more extensive over time. To test this hypothesis, we treated rats subcutaneously with 1, 2, 3 or 4 g/kg of HPβCD and waited for 8-weeks to assess the long-term histological consequences. Our new results indicate that the two highest doses of HPβCD caused extensive damage not only to OHC, but also to inner hair cells, pillar cells and other support cells resulting in the collapse and flattening of the sensory epithelium. The 4 g/kg dose destroyed all the outer hair cells and three-fourths of the inner hair cells over the basal two-thirds of the cochlea and more than 85% of the nerve fibers in the habenula perforata and more than 80% of spiral ganglion neurons in the middle of basal turn of the cochlea. The mechanisms that lead to the delayed degeneration of inner hair cells, pillar cells, nerve fibers and spiral ganglion neurons remain poorly understood, but may be related to the loss of trophic support caused by the degeneration of sensory and/or support cells in the organ of Corti. Despite the massive damage to the cochlear sensory epithelium, the blood vessels in the stria vascularis and the vestibular hair cells in the utricle and saccule remained normal.

Exposure to diphtheria toxin during the juvenile period impairs both inner and outer hair cells in C57BL/6 mice

Diphtheria toxin (DT) administration into transgenic mice that express the DT receptor (DTR) under control of specific promoters is often used for cell ablation studies in vivo. Because DTR is not expressed in mice, DT injection has been assumed to be nontoxic to cells in vivo. In this study, we demonstrated that DT application during the juvenile stage leads to hearing loss in wild-type mice. Auditory brainstem response measurement showed severe hearing loss in C57BL/6 mice administered DT during the juvenile period, and the hearing loss persisted into adulthood. However, ototoxicity did not occur when DT was applied on postnatal day 28 or later. Histological studies demonstrated that hearing loss was accompanied by significant degeneration of inner and outer hair cells (HCs), as well as spiral ganglion neurons. Scanning electron microscopy showed quick degeneration of inner HCs within 3days and gradual degeneration of outer HCs within 1week. These results demonstrated that DT has ototoxic action on C57BL/6 mice during the juvenile period, but not thereafter, and the hearing loss was due to degeneration of inner and outer HCs by unknown DT-related mechanisms.

Delayed loss of hearing after hearing preservation cochlear implantation: Human temporal bone pathology and implications for etiology

After initially successful preservation of residual hearing with cochlear implantation, some patients experience subsequent delayed hearing loss. The etiology of such delayed hearing loss is unknown. Human temporal bone pathology is critically important in investigating the etiology, and directing future efforts to maximize long term hearing preservation in cochlear implant patients. Here we present the temporal bone pathology from a patient implanted during life with an Iowa/Nucleus Hybrid S8 implant, with initially preserved residual hearing and subsequent hearing loss. Both temporal bones were removed for histologic processing and evaluated. Complete clinical and audiologic records were available. He had bilateral symmetric high frequency severe to profound hearing loss prior to implantation. Since he was implanted unilaterally, the unimplanted ear was presumed to be representative of the pre-implantation pathology related to his hearing loss. The implanted and contralateral unimplanted temporal bones both showed complete degeneration of inner hair cells and outer hair cells in the basal half of the cochleae, and only mild patchy loss of inner hair cells and outer hair cells in the apical half. The total spiral ganglion neuron counts were similar in both ears: 15,138 (56% of normal for age) in the unimplanted right ear and 13,722 (51% of normal for age) in the implanted left ear. In the basal turn of the implanted left cochlea, loose fibrous tissue and new bone formation filled the scala tympani, and part of the scala vestibuli. Delayed loss of initially preserved hearing after cochlear implantation was not explained by additional post-implantation degeneration of hair cells or spiral ganglion neurons in this patient. Decreased compliance at the round window and increased damping in the scala tympani due to intracochlear fibrosis and new bone formation might explain part of the post-implantation hearing loss. Reduction of the inflammatory and immune response to cochlear implantation may lead to better long term hearing preservation post-implantation.

Glutamate agonist causes irreversible degeneration of inner hair cells

Glutamate neurotoxicity in cochlear hair cells was investigated by administering the glutamate agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) into the scala tympani of Mongolian gerbils. AMPA administration caused the formation of large number of vacuoles in the inner hair cells (IHCs) and dendritic terminals. The number of degenerated hair cells was counted using rhodamine-phalloidin and Hoechst 33342 staining. The administration of 50 microM AMPA caused reversible elevation of the auditory brainstem response threshold without loss of IHCs. In contrast, 200 microM AMPA induced a substantial elevation of the auditory brainstem response threshold with the characteristic disappearance of IHCs. As cochlear ischemia involves excessive glutamate release, these results suggest that an elevated glutamate level in the cochlea is responsible for the progressive IHC death related to ischemic injury.

Multiple Quantitative Trait Loci Modify Cochlear Hair Cell Degeneration in the Beethoven (Tmc1Bth) Mouse Model of Progressive Hearing Loss DFNA36

Dominant mutations of transmembrane channel-like gene 1 (TMC1) cause progressive sensorineural hearing loss in humans and Beethoven (Tmc1Bth/+) mice. Here we show that Tmc1Bth/+ mice on a C3HeB/FeJ strain background have selective degeneration of inner hair cells while outer hair cells remain structurally and functionally intact. Inner hair cells primarily function as afferent sensory cells, whereas outer hair cells are electromotile amplifiers of auditory stimuli that can be functionally assessed by distortion product otoacoustic emission (DPOAE) analysis. When C3H-Tmc1Bth/Bth is crossed with either C57BL/6J or DBA/2J wild-type mice, F1 hybrid Tmc1Bth/+ progeny have increased hearing loss associated with increased degeneration of outer hair cells and diminution of DPOAE amplitudes but no difference in degeneration of inner hair cells. We mapped at least one quantitative trait locus (QTL), Tmc1m1, for DPOAE amplitude on chromosome 2 in [(C/B)F1xC]N2-Tmc1Bth/+ backcross progeny, and three other QTL on chromosomes 11 (Tmc1m2), 12 (Tmc1m3), and 5 (Tmc1m4) in [(C/D)F1xC]N2-Tmc1Bth/+ progeny. The polygenic basis of outer hair cell degeneration in Beethoven mice provides a model system for the dissection of common, complex hearing loss phenotypes, such as presbycusis, that involve outer hair cell degeneration in humans.

Kanamycin ototoxicity in glutamate transporter knockout mice

Glutamate-aspartate transporter (GLAST), a powerful glutamate uptake system, removes released glutamate from the synaptic cleft and facilitates the re-use of glutamate as a neurotransmitter recycling system. Aminoglycoside-induced hearing loss is mediated via a glutamate excitotoxic process. We investigated the effect of aminoglycoside ototoxicity in GLAST knockout mice using the recorded auditory brainstem response (ABR) and number of hair cells in the cochlea. Kanamycin (100 mg/mL) was injected directly into the posterior semicircular canal of mice. Before the kanamycin treatment, there was no difference in the ABR threshold average between the wild-type and knockout mice. Kanamycin injection aggravated the ABR threshold in the GLAST knockout mice compared with the wild-type mice, and the IHC degeneration was more severe in the GLAST knockout mice. These findings suggest that GLAST plays an important role in preventing the degeneration of inner hair cells in aminoglycoside ototoxicity.

Abortive synaptogenesis as a factor in the inner hair cell degeneration in the Bronx Waltzer (bv) mutant mouse.

The Bronx Waltzer (vb) mutation in the mouse results in the degeneration of most but not all of the primary auditory receptors, the inner hair cells, and their afferent neurons. We analyzed the ultrastructure of 94 inner hair cells in the intact postnatal mutant mouse and in neonatal cochleas in culture to understand the pathogenesis of hair cell death and to detect factors that may prevent it. The vb spiral neurons of the Bronx Waltzer display two distinctive features: some of them continue to divide mitotically for at least seven postnatal days, and the type I radial fibers that innervate inner hair cells display a deficiency in immunoexpression of GAD. The growing endings of spiral neurons converge around the inner hair cells or, in their absence, invade the outer hair cell region. Their profuse sprouting among inner spiral sulcus cells contributes to the characteristic ultrastructural picture of the bv cochlea. During the first three days after birth, 40% of the inner hair cells appear normal and innervated, 40% are mostly denervated and degenerating, and 20% are immature, with minimal or no neuronal appositions. However, in mutants 6 days and older only a few inner hair cells survive, and these show either normal or superfluous afferent innervation and axosomatic GABAergic efferent innervation. Degeneration of inner hair cells begins with a distention of the nuclear envelope and the ribosomal endoplasmic reticulum. The outer nuclear membrane eventually breaks, and exudate fills the cell interior. The cellular edema leads to cell death. We propose that success or failure in synaptic acquisition is a decisive factor in the survival or decline of the mutant inner hair cells. We also suggest that the developmental delay in maturation of the spiral ganglion neurons (type I) and the failure in their synaptogenesis may be caused by an impairment in neurotrophin (NT3/BDNF) synthesis by their mutant receptor cells.