Null mutation of α1D Ca2+ channel gene results in deafness but no vestibular defect in mice

Multiple Ca2+ channels confer diverse functions to hair cells of the auditory and vestibular organs in the mammalian inner car. We used gene-targeting technology to generate alpha(1)D Ca2+ channel-deficient mice to determine the physiological role of these Ca2+ channels in hearing and balance. Analyses of auditory-evoked brainstem recordings confirmed that alpha(1D)(-/-) mice were deaf and revealed that heterozygous mice have increased hearing thresholds. However, hearing deficits in alpha(1D)(+/-) mice were manifested mainly by the increase in threshold of low-frequency sounds. In contrast to impaired hearing, alpha(1D)(-/-) Juice have balance performances equivalent to their wild-type littermates, Light and electron microscope analyses of the inner ear revealed outer hair cell loss at the apical cochlea, but no apparent abnormality at the basal cochlea and the vestibule. We determined the mechanisms underlying the auditory function defects and the normal vestibular functions by examining the Ba2+ currents in cochlear inner and outer hair cells versus utricular hair cells in mice. Whereas the whole-cell Ba2+ Currents in inner hair cells consist mainly of the nimodipine-sensitive current (similar to85%), the utricular hair cells express only similar to50% of this channel subtype. Thus, differential expression of alpha(1D) channels in the cochlear and utricular hair cells confers the phenotype of the alpha(1D) null mutant Juice. Because vestibular and cochlear hair cells share common features and null deletion of several genes have yielded both deafness and imbalance in mice, alpha(1D) null mutant mice may serve as a model to disentangle vestibular from auditory-specific functions.