Mice heterozygous for the Cdh23/Ahl1 mutation show age-related deficits in auditory temporal processing

A mutation in the Cdh23 gene is implicated in both syndromic and nonsyndromic hearing loss in humans and age-related hearing loss in C57BL/6 mice. It is generally assumed that human patients (as well as mouse models) only have a hearing loss phenotype if the mutation is homozygous. However, a major complaint for patients with a hearing disability is a reduced speech intelligibility that may be related to temporal processing deficits rather than just elevated thresholds. In this study, we used the amplitude modulation following response (AMFR) to test whether mice heterozygous for Cdh23^{735A > G} have an auditory phenotype that includes temporal processing deficits. The hearing of mice heterozygous for the Cdh23^{735A > G} mutation was compared with age-matched mice homozygous for either the mutation or the wild type in 3 cohorts of mice of both sexes at 2-3, 6, and 12 months of age. The AMFR technique was used to generate objective hearing thresholds for all mice across their range of hearing and to test their temporal processing. We found a genotype-dependent hearing loss in mice homozygous for the mutation starting at 5-11 weeks of age, an age when mice on the C57BL/6 background are often presumed to have normal hearing. The heterozygous animals retained normal hearing thresholds up to one year of age. Nevertheless, the heterozygous animals showed a decline in temporal processing abilities at one year of age that was independent of their hearing thresholds. These results suggest that mice heterozygous for the Cdh23 mutation do not have truly normal hearing.