Stereocilin-deficient mice reveal the origin of cochlear waveform distortions

Abstract

Although the cochlea is an amplifier and a remarkably sensitive and finely tuned detector of sounds, it also produces conspicuous mechanical and electrical waveform distortions1. These distortions reflect non-linear mechanical interactions within the cochlea. By allowing one tone to suppress another (masking effect), they contribute to speech intelligibility2. Tones can also combine to produce sounds with frequencies not present in the acoustic stimulus3. These sounds compose the otoacoustic emissions that are extensively used to screen hearing in newborns. As both cochlear amplification and distortion originate from the outer hair cells, one of the two types of sensory receptor cells, it has been speculated that they stem from a common mechanism. Here, the non-linearity underlying cochlear waveform distortions is shown to rely on the presence of stereocilin, a protein defective in a recessive form of human deafness4. Stereocilin was detected in association with horizontal top connectors5-7, lateral links that join adjacent stereocilia within the outer hair cell’s hair bundle, and these links were absent in stereocilin-null mutant mice. These mice become progressively deaf. At the onset of hearing, however, their cochlear sensitivity and frequency tuning were almost normal, although masking was much reduced and both acoustic and electrical waveform distortions were completely lacking. From this unique functional situation, we conclude that the main source of cochlear waveform distortions is a deflection-dependent hair bundle stiffness resulting from constraints imposed by the horizontal top connectors, and not from the intrinsic non-linear behaviour of the mechanoelectrical transducer channel.

A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation

“…Otoancorin is not expressed in OHCs, and another protein must therefore mediate adhesion of the OHC stereocilia to the TM. Although otoancorin and stereocilin share some long-range homology (33), and despite the absence of hair-bundle imprints in the TMs of stereocilin null mice (25), functional interactions between the TM and the OHCs do not require stereocilin (34). Distinct molecular mechanisms may therefore mediate interactions between the TM and the OHCs, but also between the TM and the spiral limbus.…”

“…The timing of the forces that are fed back to the cochlear partition by the OHCs is crucial for cochlear amplification to be effective (20,(33)(34)(35), and depends on whether the OHC hair bundles are driven by the elastic or inertial forces delivered by the TM (33). For frequencies well below the characteristic frequency (CF; i.e., the frequency that produces the most sensitive response), the TM imposes an elastic load on the OHC bundles and they are displaced maximally in the excitatory direction (i.e., toward the tallest row of stereocilia) during maximum displacement of the cochlear partition toward the scala vestibuli (1,(36)(37)(38)(39)(40).…”

Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

“…ABRs, CM, and DPOAEs were recorded in anesthetized mice and analyzed as described previously (34,35).…”

Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with α-tectorin and is mutated in autosomal dominant hearing loss (DFNA4)

“…Electron microscopy resolves attachment links that form a TM-attachment crown around the tips of the tallest OHC stereocilia, connecting them to the undersurface of the TM (19). Although stereocilin may be associated with the crown (20), other possible TM crown components have not been identified. It is known, however, that the crown is susceptible to digestion by subtilisin but is not sensitive to calcium chelation with 1,2-bis(oaminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) (21).…”