Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model
Luis R. Cassinotti, Lingchao Ji, M. Caroline Yuk, Aditi S. Desai, Nathan D. Cass, Zahara A. Amir, Gabriel Corfas
Luis R. Cassinotti, Lingchao Ji, M. Caroline Yuk, Aditi S. Desai, Nathan D. Cass, Zahara A. Amir, Gabriel Corfas
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Research Article Neuroscience Otology

Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model

Abstract

Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound-evoked cochlear compound action potentials, has been proposed to contribute to hearing difficulty in noisy environments in people with normal hearing thresholds and has become a widespread complaint. While most studies on HHL pathogenesis have focused on inner hair cell (IHC) synaptopathy, we recently showed that transient auditory nerve (AN) demyelination also causes HHL in mice. To test the effect of myelinopathy on hearing in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibited the functional hallmarks of HHL together with disorganization of AN heminodes near the IHCs with minor loss of AN fibers. These results support the hypothesis that mild disruptions of AN myelination can cause HHL and that heminodal defects contribute to the alterations in the sound-evoked cochlear compound action potentials seen in this mouse model. Furthermore, these findings suggest that patients with CMT1A or other mild peripheral neuropathies are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in patients with CMT1A might help develop robust clinical tests for HHL, which are currently lacking.

Authors

Luis R. Cassinotti, Lingchao Ji, M. Caroline Yuk, Aditi S. Desai, Nathan D. Cass, Zahara A. Amir, Gabriel Corfas

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Figure 3

CMT1A and CMT1E mice have distinct myelin and axonal pathologies.

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CMT1A and CMT1E mice have distinct myelin and axonal pathologies. (A) Re...
(A) Representative electron micrographs of sections through the OSL showing an axon bundle (top), a high-magnification image of the axons (middle), and an individual myelinated axon image (bottom) from 4-month-old WT (left), CMT1A (center), and CMT1E (right) mice. Scale bars: 4 μm (top), 1 μm (middle), 200 nm (bottom).(B) CMT1A and CMT1E animals have different degrees of myelinated axons loss — 19% and 78%, respectively — compared with WT mice. Dots represent the number of myelinated axons per 100 μm2 cross section through the OSL at 16 kHz per mouse (n = 3 cochleae per genotype). (C) Frequency histogram showing that CMT1A mice have a larger number of small diameter axons than WT mice. Inset: CMT1A mice have a 16% reduction in axon diameter versus WT. Each dot represents the averaged axon diameter per experimental animal (n = 3 cochleae per genotype). (D) CMT1E mice have decreased myelin thickness (g-ratio = 0.735) compared with WT (g-ratio = 0.633) and CMT1A mice (g-ratio = 0.633). Each dot represents the averaged g-ratio per experimental animal (n = 3 cochleae per genotype) (E) CMT1E hypomyelination is independent of axon diameter while CMT1A mice have an increased steepening in the regression line in the g-ratio versus axon diameter graph (n = 3 cochleae per genotype at the 16 kHz region; WT axons = 201–253 per cochlea, CMT1A axons = 138–198 per cochlea, CMT1E axons = 62–146 per cochlea). Quantification of myelinated axon densities, axon diameters, and g-ratios were analyzed by 1-way ANOVA followed by Tukey’s multiple-comparison test. Linear regression and differences among slopes of axon diameters versus g-ratio plots were obtained with GraphPad Prism simple linear regression test. *P < 0.05; ****P < 0.0001. Data are shown as mean ± SEM.