Age-related hearing loss and the ahl locus in mice

Abstract

C57BL/6 (B6) mice experience hearing loss and cochlear degeneration beginning about mid-life, whereas CAST/Ei (CAST) mice retain normal hearing until old age. A locus contributing to the hearing loss of B6 mice, named age-related hearing loss (ahl), was mapped to Chromosome 10. A homozygous, congenic strain of mice (B6.CAST-+ahl ), generated by crossing B6 (ahl/ahl) and CAST (+ahl/+ahl) mice has the same genomic material as the B6 mice except in the region of the ahl locus, which is derived from CAST. In this study, we have determined the extent of the CAST-derived region of Chromosome 10 in the congenic strain and have examined mice of all three strains for hearing loss and cochlear morphology between 9 and 25 months of age. Results for B6 mice were similar to those described previously. CAST mice showed no detectable hearing loss even at 24 months of age; however, they had a small amount of ganglion cell degeneration. B6.CAST-+ahl mice were protected from early onset hearing loss and basal turn degeneration, but older animals did show some hearing loss and ganglion cell degeneration. We conclude that loci in addition to ahl contribute to the differences in hearing loss between B6 and CAST mice. These results illustrate the complex inheritance of age-related hearing loss in mice and may have implications for the study of human presbycusis.

Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis

“…It is also well known that C57BL/6J mice respond to CR with a robust extension of lifespan (17), in agreement with our observation that CR prevents AHL in this strain (6). C57BL/6J and many mouse strains that display AHL carry a specific mutation (Cdh23 753A ) in the Cdh23 gene, which encodes a component of the hair-cell tip link (5,8,9). The mutation is a hypomorphic allele that leads to a disorganized hair bundle (9).…”

“…However, the C57BL/6J strain displays the classic pattern of AHL (4, 5, 7), similar to that reported in humans (1,38) and in the CBA/J mouse strain that does not possess the Cdh23 753A mutation and displays late onset of AHL by 18 months of age (4,7,39). In both strains, the onset of AHL begins in the high-frequency region and spreads toward the low frequencies with age, and the loss of hair cells and neurons begins in the base and spreads toward the apex of the cochlea with age (4,5,7,39). Thus, the Cdh23 753A allele affects age of onset of AHL, but the basic mechanisms of cochlear aging are likely to be similar in C57BL/6J and CBA/J strains.…”

“…Decreased SG neuron density and hair cell numbers are hallmarks of AHL (5). The hair cells that transduce sound relay their electrical response postsynaptically to SG neurons, which in turn transmit the neural signal through the auditory neuraxis to the auditory cortex, where the information is interpreted (23).…”

“…The C57BL/6J mouse strain, which is widely used for aging research, displays the classic pattern of AHL by 12 to 15 months of age (5)(6)(7). The onset of AHL in this strain begins in the highfrequency region and spreads toward the low frequencies with age; these functional deficits are accompanied by the loss of hair cells and neurons that begins in the base and spread toward the apex of the cochlea with age (5,7). Strains susceptible to early-onset AHL, including C57BL/6J, are known to carry a specific mutation in the cadherin 23 gene (Cdh23), which encodes a component of the hair-cell tip link (5,8,9).…”

A mouse model with postnatal endolymphatic hydrops and hearing loss

“…In these cases, primary neuronal loss is linked to changes in supporting cells and Reissner's membrane. Though hydrops has not been reported in aging mouse models, it has been proposed that the changes in supporting cells and Reissner's membrane may be due to disorders of inner ear fluid homeostasis (Keithley et al, 2004;Ohlemiller and Gagnon, 2004;Willott and Erway, 1998). Due to the presence of hydrops in the young Phex Hyp-Duk /Y mutants (P21-90), one might expect a defect in cochlear fluid balance associated with strial pathology.…”