Auditory Neuropathy after Damage to Cochlear Spiral Ganglion Neurons in Mice Resulting from Conditional Expression of Diphtheria Toxin Receptors

Abstract

Auditory neuropathy (AN) is a hearing disorder characterized by normal cochlear amplification to sound but poor temporal processing and auditory perception in noisy backgrounds. These deficits likely result from impairments in auditory neural synchrony; such dyssynchrony of the neural responses has been linked to demyelination of auditory nerve fibers. However, no appropriate animal models are currently available that mimic this pathology. In this study, Cre-inducible diphtheria toxin receptor (iDTR +/+) mice were cross-mated with mice containing Cre (Bhlhb5-Cre +/−) specific to spiral ganglion neurons (SGNs). In double-positive offspring mice, the injection of diphtheria toxin (DT) led to a 30–40% rate of death for SGNs, but no hair cell damage. Demyelination types of pathologies were observed around the surviving SGNs and their fibers, many of which were distorted in shape. Correspondingly, a significant reduction in response synchrony to amplitude modulation was observed in this group of animals compared to the controls, which had a Cre− genotype. Taken together, our results suggest that SGN damage following the injection of DT in mice with Bhlhb5-Cre +/− and iDTR +/− is likely to be a good AN model of demyelination.

Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss

“…Thus, Mpz, is expressed in the spiral ganglion and cochlear nerve as the major component of the peripheral nervous system myelin sheath (Wang et al, 2013). The RNA-binding RbFox3/NeuN- coding nuclear factor is expressed in post-mitotic neurons and is involved in the development and maintenance of neuronal functions (Lin et al, 2016; Pan et al, 2017). The transcription factor Sox2 is required for inner ear development and is expressed by Schwan cells and supporting cells in the adult cochlea (Hume et al, 2007; Steevens et al, 2017).…”

Deletion of Kcnj16 in Mice Does Not Alter Auditory Function

“…Three subdermal electrodes were placed at the vertex (recording), ipsilateral mastoid (reference), and contralateral hind limb (ground). A TDT System III workstation running SigGen32 software (Tucker-Davis Technologies, United States) was used to generate tone burst stimuli at 4, 8, 12, 16, and 32 kHz ( Han et al, 2016 ; Pan et al, 2017 ). For each frequency, the sound level was decreased in 5-dB steps from 90 to 10 dB SPL.…”

Deletion of Limk1 and Limk2 in mice does not alter cochlear development or auditory function

“…A TDT System III workstation running SigGen32 software (Tucker-Davis Technologies, USA) was used to test mice for ABR and CAP recordings as previously described 3,14,67 . Mice were anesthetized using 10 mg/kg xylazine and 80 mg/kg ketamine, and the body temperature was kept at 38 °C with a thermostatic heating pad.…”