An unusually powerful mode of low-frequency sound interference due to defective hair bundles of the auditory outer hair cells

Abstract

A detrimental perceptive consequence of damaged auditory sensory hair cells consists in a pronounced masking effect exerted by low-frequency sounds, thought to occur when auditory threshold elevation substantially exceeds 40 dB. Here, we identified the submembrane scaffold protein Nherf1 as a hair-bundle component of the differentiating outer hair cells (OHCs). Nherf1 −/− mice displayed OHC hair-bundle shape anomalies in the mid and basal cochlea, normally tuned to mid-and high-frequency tones, and mild (22-35 dB) hearing-threshold elevations restricted to midhigh sound frequencies. This mild decrease in hearing sensitivity was, however, discordant with almost nonresponding OHCs at the cochlear base as assessed by distortion-product otoacoustic emissions and cochlear microphonic potentials. Moreover, unlike wild-type mice, responses of Nherf1 −/− mice to high-frequency (20-40 kHz) test tones were not masked by tones of neighboring frequencies. Instead, efficient maskers were characterized by their frequencies up to two octaves below the probe-tone frequency, unusually low intensities up to 25 dB below probe-tone level, and growth-ofmasker slope (2.2 dB/dB) reflecting their compressive amplification. Together, these properties do not fit the current acknowledged features of a hypersensitivity of the basal cochlea to lower frequencies, but rather suggest a previously unidentified mechanism. Low-frequency maskers, we propose, may interact within the unaffected cochlear apical region with midhigh frequency sounds propagated there via a mode possibly using the persistent contact of misshaped OHC hair bundles with the tectorial membrane. Our findings thus reveal a source of misleading interpretations of hearing thresholds and of hypervulnerability to low-frequency sound interference.off-frequency detection | Usher syndrome | hearing impairment | Nherf2 | tail hypersensitivity M ammalian hearing displays remarkable sensitivity, fine temporal acuity, and exquisite frequency selectivity, which contribute to auditory scene analysis and speech intelligibility. The first steps of sound processing, i.e., sound wave detection and neuronal encoding in the cochlea, are performed by two populations of hair cells, the inner hair cells (IHCs) and the outer hair cells (OHCs). These cells are sandwiched between the underlying basilar membrane (BM) and the overlying tectorial membrane (TM) (SI Appendix, Fig. S1A). IHCs are the genuine sensory cells that transduce the sound stimuli into electrical signals in the primary auditory neurons. OHCs are mechanical effectors that amplify the sound-evoked movements of the cochlear partition, sharpen its frequency selectivity, and produce waveform distortions (1, 2). A pure-tone stimulus entering the cochlea elicits a traveling wave that propagates along the BM from the cochlear base toward its apex, increasing in amplitude until it peaks at a characteristic place, where the mechanical properties of the cochlea are best tuned to the stimulus frequency. Beyond this characteristic place, the ampl...

The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing

“…RDX is a member of the ERM protein family and thought to act as a molecular linker between cytoskeletal actin, the plasma membrane, and intrinsic membrane proteins . Prompted by these phenotypic similarities, we assessed stereociliar RDX levels in Lrba mutant OHC hair bundles using semi‐quantitative immunofluorescence analysis with specific antibodies against RDX (for RDX antibody validation, please refer to Appendix Fig S4) and the two RDX‐binding proteins Nherf1 and Nherf2 (Fig ). In these measurements, we found a reduction in stereociliar RDX levels to ~50% of wild‐type levels (Fig A, B, and G) alongside a smaller, but statistically significant reduction in the RDX‐interacting protein Nherf2 to ~85% of control (Fig C, D, and H).…”

Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome

“…Total RNA (100 ng) was reverse-transcribed with the SuperScript III One-Step RT-PCR system (Invitrogen) as described by the manufacturer using various isoform-specific primers (see Supplemental Methods). For expression vectors, antibodies, protein-protein interactions (47), immunofluorescence (48), and electron microscopy analyses (49), see Supplemental Methods.…”

Controllable Activation of Nanoscale Dynamics in a Disordered Protein Alters Binding Kinetics

“…NHERF1 is also necessary for assembling microvillus structure in epithelial cells [16–18]. NHERF1 knockout mice have defective auditory hair cell structure and exhibit impaired hearing [19]. …”