CACHD1-deficient mice exhibit hearing and balance deficits associated with a disruption of calcium homeostasis in the inner ear.

CACHD1 recently was shown to be an α2δ-like subunit that can modulate the activity of some types of voltage-gated calcium channels, including the low-voltage activated, T-type CaV3 channels. CACHD1 is widely expressed in the central nervous system but its biological functions and relationship to disease states are unknown. Here, we report that mice with deleterious Cachd1 mutations are hearing impaired and have balance defects, demonstrating that CACHD1 is functionally important in the peripheral auditory and vestibular organs of the inner ear. The vestibular dysfunction of Cachd1 mutant mice, exhibited by leaning and head tilting behaviors, is related to a deficiency of calcium carbonate crystals (otoconia) in the saccule and utricle. The auditory dysfunction, shown by ABR threshold elevations and reduced DPOAEs, is associated with reduced endocochlear potentials and increased endolymph calcium concentrations. Paint-fills of mutant inner ears from prenatal and newborn mice revealed dilation of the membranous labyrinth caused by an enlarged volume of endolymph. These pathologies all can be related to a disturbance of calcium homeostasis in the endolymph of the inner ear, presumably caused by the loss of CACHD1 regulatory effects on voltage-gated calcium channel activity. Cachd1 expression in the cochlea appears stronger in late embryonic stages than in adults, suggesting an early role in establishing endolymph calcium concentrations. Our findings provide new insights into CACHD1 function and suggest the involvement of voltage-gated calcium channels in endolymph homeostasis, essential for normal auditory and vestibular function

Estimating the operating point of the cochlear transducer using low-frequency biased distortion products

Distortion products in the cochlear microphonic (CM) and in the ear canal in the form of distortion product otoacoustic emissions (DPOAEs) are generated by nonlinear transduction in the cochlea and are related to the resting position of the organ of Corti (OC). A 4.8 Hz acoustic bias tone was used to displace the OC, while the relative amplitude and phase of distortion products evoked by a single tone [most often 500 Hz, 90 dB SPL (sound pressure level)] or two simultaneously presented tones (most often 4 kHz and 4.8 kHz, 80 dB SPL) were monitored. Electrical responses recorded from the round window, scala tympani and scala media of the basal turn, and acoustic emissions in the ear canal were simultaneously measured and compared during the bias. Bias-induced changes in the distortion products were similar to those predicted from computer models of a saturating transducer with a first-order Boltzmann distribution. Our results suggest that biased DPOAEs can be used to non-invasively estimate the OC displacement, producing a measurement equivalent to the transducer operating point obtained via Boltzmann analysis of the basal turn CM. Low-frequency biased DPOAEs might provide a diagnostic tool to objectively diagnose abnormal displacements of the OC, as might occur with endolymphatic hydrops