Reduction in noise-induced functional loss of the cochleae in mice with pre-existing cochlear dysfunction due to genetic interference of prestin.

Qunfeng Cai,Donald Coling,Bo Wang,Bo Hua Hu,Jian Zuo,Shiming Yang,Krystal Vera,Jie Fang,Makoto Sato

doi:10.1371/journal.pone.0113990

Abstract

Various cochlear pathologies, such as acoustic trauma, ototoxicity and age-related degeneration, cause hearing loss. These pre-existing hearing losses can alter cochlear responses to subsequent acoustic overstimulation. So far, the knowledge on the impacts of pre-existing hearing loss caused by genetic alteration of cochlear genes is limited. Prestin is the motor protein expressed exclusively in outer hair cells in the mammalian cochlea. This motor protein contributes to outer hair cell motility. At present, it is not clear how the interference of prestin function affects cochlear responses to acoustic overstimulation. To address this question, a genetic model of prestin dysfunction in mice was created by inserting an internal ribosome entry site (IRES)-CreERT2-FRT-Neo-FRT cassette into the prestin locus after the stop codon. Homozygous mice exhibit a threshold elevation of auditory brainstem responses with large individual variation. These mice also display a threshold elevation and a shift of the input/output function of the distortion product otoacoustic emission, suggesting a reduction in outer hair cell function. The disruption of prestin function reduces the threshold shifts caused by exposure to a loud noise at 120 dB (sound pressure level) for 1 h. This reduction is positively correlated with the level of pre-noise cochlear dysfunction and is accompanied by a reduced change in Cdh1 expression, suggesting a reduction in molecular responses to the acoustic overstimulation. Together, these results suggest that prestin interference reduces cochlear stress responses to acoustic overstimulation.

Highlights

Acoustic overstimulation is a common cause of sensory cell damage in the cochlea
The homozygous mice exhibited a flat threshold elevation with an average of 16–21 dB shift across the four tested frequencies, compared with those of the wild-type mice (Fig. 1A; two-way analysis of variance (ANOVA), F1,3845121.0, P,0.001; Tukey test, P,0.001 for all of the test frequency points). These observations suggest that insertion of CreERT2 into one allele does not induce a significant loss of hearing sensitivity, whereas the insertion of Prestin-CreERT2 into two alleles reduces the hearing sensitivity
Because the up-regulation of Cdh1 is a molecular response to acoustic overstimulation [24], our results suggest that the Prestin-CreERT2 knockin-induced outer hair cell (OHC) dysfunction reduced the molecular responses of the organ of Corti to acoustic trauma

Summary

Introduction

While the magnitude of acoustic trauma is associated with the properties of noise, the final outcome of cochlear degeneration is related to the functional status of the cochlea at the time of noise exposure [1,2,3]. Various pathological conditions, such as aging degeneration, ototoxicity and acoustic trauma, can compromise cochlear function, which in turn alters cochlear responses to subsequent acoustic overstimulation. On the other hand, potentiates cochlear damage to subsequent noise injury [12] This effect occurs at the frequency region that is not damaged by the initial noise trauma [1]. These observations suggest that the pre-existing cochlear dysfunction can affect the pattern of subsequent cochlear degeneration due to acoustic overstimulation

Methods

Results

Conclusion