Effect of PMCA2 mutation on cochlear responses and their development in deafwaddler mice

The effects of the deafwaddler mutation (dfw) on cochlear response properties are examined in adult mice aged 60 dab and in developing mice from 10 to 30 days old. Deafwaddler is a spontaneous genetic mutation that causes cochlear and vestibular hair cell damage. These mice are congenitally deaf as part of a syndrome which includes vestibular dysfunction. Hearing loss in heterozygotes (+/dfw) is frequency-specific and appears to be nonsyndromic. It is now known that dfw alters a gene encoding a plasma membrane Ca2+ ATP-ase (PMCA2) (Street, McKee-Johnson, Fonseca, Tempel, & Noben-Trauth, 1998).; In order to characterize the effect of dfw on OHC-system function, DPOAEs were examined in adult control mice, dfw mutants, and in control mice treated with the drug furosemide. Homozygous mice did not have measurable emissions. Heterozygotes had reduced or absent DPOAEs at moderate and high stimulus frequencies. Where present, emissions at these frequencies were significantly reduced at moderate as well as at high stimulus levels. Additionally, group delays were longer in +/ dfw than in controls over a wide range of frequencies. DPOAE amplitudes were only reduced at moderate stimulus intensities in furosemide-treated controls. High level stimuli evoked DPOAEs that were similar to pre-injection values. Emission latencies (group delays) were unaffected. DPOAE amplitude by f2/f1 ratio functions (filter functions) retained their shape in +/dfw mice and in furosemide-treated controls.; Hearing function in developing dfw mutants and control mice was examined using a number of responses (DPOAEs, CMDPs, SPs, and CAPs) measured simultaneously within a given animal. Responses were not present in young postnatal dfw/dfw mice. Auditory development in +/dfw mice appears normal through 16 dab. By 20 dab, DPOAE and CMDP responses to high frequencies were reduced compared to age-matched controls. In addition, the negative SP is significantly reduced at high frequencies and CAP amplitudes were large relative to controls at low to mid frequencies in +/dfw mice. Results suggest that PMCA2 is required for the development and maintenance of hearing.