Dataset Information

Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice.

ABSTRACT: Both the ahl allele of Cdh23 and the null mutation of Sod1 have been shown to contribute to age-related hearing loss (AHL) in mice, but mixed strain backgrounds have confounded analyses of their individual and combined effects. To test for the effects of Sod1 deficiency independently from those of Cdh23(ahl), we produced mice with four digenic genotypes: Sod1(+/+)Cdh23(ahl)(/ahl), Sod1(+/+)Cdh23(+/+), Sod1(-/-)Cdh23(ahl)(/ahl), and Sod1(-/-)Cdh23(+/+), all on a uniform C57BL(/)6J strain background. We assessed hearing loss by ABR threshold measurements and evaluated cochlear pathologies in age-matched mice of each digenic combination. ABR analysis showed that Sod1(+/+)Cdh23(+/+) mice retain normal hearing up to 15 months of age and that hearing loss of Sod1(+/+)Cdh23(ahl)(/ahl) mice is more age and frequency dependent than that of Sod1(-/-)Cdh23(+/+) mice. ABR results also showed that mice with both gene mutations (Sod1(-/-)Cdh23(ahl)(/ahl)) exhibit the earliest onset and most severe hearing loss, greater than predicted for strictly additive effects. Histological analysis of cochleas showed that hair cell lesions are most severe in Sod1(-)(/-)Cdh23(ahl)(/ahl) mice followed closely by Sod1(+)(/+)Cdh23(ahl)(/ahl) mice and much smaller in Sod1(-)(/-)Cdh23(+)(/+) and Sod1(+)(/+)Cdh23(+)(/+) mice. Despite extensive damage to cochlear hair cells, vestibular hair cells appeared remarkably normal in all strains. Although both Sod1(-/-) and Cdh23(ahl)(/ahl) genotypes had strong effects on hearing loss, the Cdh23(ahl/ahl) genotype was primarily responsible for the increase in hair cell loss, suggesting that the two mutations have different underlying mechanisms of pathology.

SUBMITTER: Johnson KR

PROVIDER: S-EPMC2923272 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice.

Johnson Kenneth R KR Yu Heping H Ding Dalian D Jiang Haiyan H Gagnon Leona H LH Salvi Richard J RJ

Hearing research 20100512 1-2

Both the ahl allele of Cdh23 and the null mutation of Sod1 have been shown to contribute to age-related hearing loss (AHL) in mice, but mixed strain backgrounds have confounded analyses of their individual and combined effects. To test for the effects of Sod1 deficiency independently from those of Cdh23(ahl), we produced mice with four digenic genotypes: Sod1(+/+)Cdh23(ahl)(/ahl), Sod1(+/+)Cdh23(+/+), Sod1(-/-)Cdh23(ahl)(/ahl), and Sod1(-/-)Cdh23(+/+), all on a uniform C57BL(/)6J strain backgrou ...[more]

PMID: 20470874

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Project description:Inbred strain variants of the Cdh23 gene have been shown to influence the onset and progression of age-related hearing loss (AHL) in mice. In linkage backcrosses, the recessive Cdh23 allele (ahl) of the C57BL/6J strain, when homozygous, confers increased susceptibility to AHL, while the dominant allele (Ahl+) of the CBA/CaJ strain confers resistance. To determine the isolated effects of these alleles on different strain backgrounds, we produced the reciprocal congenic strains B6.CBACa-Cdh23(Ahl)(+) and CBACa.B6-Cdh23(ahl) and tested 15-30 mice from each for hearing loss progression. ABR thresholds for 8 kHz, 16 kHz, and 32 kHz pure-tone stimuli were measured at 3, 6, 9, 12, 15 and 18 months of age and compared with age-matched mice of the C57BL/6J and CBA/CaJ parental strains. Mice of the C57BL/6N strain, which is the source of embryonic stem cells for the large International Knockout Mouse Consortium, were also tested for comparisons with C57BL/6J mice. Mice of the C57BL/6J and C57BL/6N strains exhibited identical hearing loss profiles: their 32 kHz ABR thresholds were significantly higher than those of CBA/CaJ and congenic strain mice by 6 months of age, and their 16 kHz thresholds were significantly higher by 12 months. Thresholds of the CBA/CaJ, the B6.CBACa-Cdh23(Ahl)(+), and the CBACa.B6-Cdh23(ahl) strain mice differed little from one another and only slightly increased throughout the 18-month test period. Hearing loss, which corresponded well with cochlear hair cell loss, was most profound in the C57BL/6J and C57BL/6NJ strains. These results indicate that the CBA/CaJ-derived Cdh23(Ahl)(+) allele dramatically lessens hearing loss and hair cell death in an otherwise C57BL/6J genetic background, but that the C57BL/6J-derived Cdh23(ahl) allele has little effect on hearing loss in an otherwise CBA/CaJ background. We conclude that although Cdh23(ahl) homozygosity is necessary, it is not by itself sufficient to account for the accelerated hearing loss of C57BL/6J mice.

Project description:It is widely accepted that even a single acute noise exposure at moderate intensity that induces temporary threshold shift (TTS) can result in permanent loss of ribbon synapses between inner hair cells and afferents. However, effects of repeated or chronic noise exposures on the cochlear synapses especially medial olivocochlear (MOC) efferent synapses remain elusive. Based on a weeklong repeated exposure model of bandwidth noise over 2-20 kHz for 2 hours at seven intensities (88 to 106 dB SPL with 3 dB increment per gradient) on C57BL/6J mice, we attempted to explore the dose-response mechanism of prolonged noise-induced audiological dysfunction and cochlear synaptic degeneration. In our results, mice repeatedly exposed to relatively low-intensity noise (88, 91, and 94 dB SPL) showed few changes on auditory brainstem response (ABR), ribbon synapses, or MOC efferent synapses. Notably, repeated moderate-intensity noise exposures (97 and 100 dB SPL) not only caused hearing threshold shifts and the inner hair cell ribbon synaptopathy but also impaired MOC efferent synapses, which might contribute to complex patterns of damages on cochlear function and morphology. However, repeated high-intensity (103 and 106 dB SPL) noise exposures induced PTSs mainly accompanied by damages on cochlear amplifier function of outer hair cells and the inner hair cell ribbon synaptopathy, rather than the MOC efferent synaptic degeneration. Moreover, we observed a frequency-dependent vulnerability of the repeated acoustic trauma-induced cochlear synaptic degeneration. This study provides a sight into the hypothesis that noise-induced cochlear synaptic degeneration involves both afferent (ribbon synapses) and efferent (MOC terminals) pathology. The pattern of dose-dependent pathological changes induced by repeated noise exposure at various intensities provides a possible explanation for the complicated cochlear synaptic degeneration in humans. The underlying mechanisms remain to be studied in the future.

Dataset Information

Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice.

Publications

Separate and combined effects of Sod1 and Cdh23 mutations on age-related hearing loss and cochlear pathology in C57BL/6J mice.

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