Progressive irreversible hearing loss is caused by stria vascularis degeneration in an Slc26a4-insufficient mouse model of large vestibular aqueduct syndrome

Abstract

Hearing loss of patients with enlargement of the vestibular aqueduct (EVA) can fluctuate or progress, with overall downward progression. The most common detectable cause of EVA is mutations of SLC26A4. We previously described a transgenic Slc26a4-insufficient mouse model of EVA in which Slc26a4 expression is controlled by doxycycline administration. Mice that received doxycycline from conception until embryonic day 17.5 (DE17.5) had fluctuating hearing loss between 1 and 6 months of age with an overall downward progression after 6 months of age. In this study, we characterized the cochlear functional and structural changes underlying irreversible hearing loss in DE17.5 mice at 12 months of age. The endocochlear potential was decreased and inversely correlated with auditory brainstem response thresholds. The stria vascularis was thickened and edematous in ears with less severe hearing loss, and thinned and atrophic in ears with more severe hearing loss. There were pathologic changes in marginal cell morphology and gene expression that were not observed at 3 months. We conclude that strial dysfunction and degeneration is the primary cause of irreversible progressive hearing loss in our Slc26a4-insufficient mouse model of EVA. This model of primary strial atrophy may be used to explore the mechanisms of progressive hearing loss due to strial dysfunction.

Slc26a4 expression prevents fluctuation of hearing in a mouse model of large vestibular aqueduct syndrome

“…Therefore we focused our quantitative analyses on the middle turn of the cochlea. Since measurements of fluorescence intensity could be influenced by differences in cell size associated with the site(s) of measurement, pathologic changes in cell size (Jabba et al, 2006; Ito et al, 2015), or both, we also measured the surface area. We calculated fluorescence intensity per unit area since the mean sizes of cells differed among the dox-administration groups.…”

“…The effector (Tg[E]; Tg(RP23-265L9/rtTA2S-M2/NeoR)1Ajg) and responder (Tg[R]; Tg(AcGFP/TRE/Slc26a4)2Ajg) transgenes were crossed with a targeted deletion allele ( Slc26a4 Δ ) of Slc26a4 to generate Tg[E];Tg[R]]; Slc26a4 Δ/ + and Tg[E];Tg[R]]; Slc26a4 Δ/Δ mice (n = 32 and 57, respectively) (Choi et al, 2011; Ito et al, 2014; Ito et al, 2015). The genetic background was mixed and included C57BL/6J, SJ/L and 129Sv/Ev.…”

“…Background fluorescence intensity was subtracted from each cell’s measured anti-pendrin fluorescence intensity for further analysis. Since measurements of fluorescence intensity could be influenced by differences in cell size associated with the site(s) of measurement, pathologic changes in cell size (Jabba et al, 2006; Ito et al, 2015), or both, fluorescence intensity per unit area was calculated for each cell. The median fluorescence intensity per unit area for cells in each group of ears was calculated and normalized to that of Tg[E];Tg[R]; Slc26a4 Δ/+ .…”

“…Many of the mice have fluctuations of hearing between 1 and 6 months of age, especially between 1 and 3 months of age, with an overall progressive hearing loss after 6 months of age (Ito et al, 2014). The fluctuation and progressive loss of hearing in Tg[E];Tg[R]; Slc26a4 Δ/Δ DE17.5 mice is caused by loss of function and degeneration of the stria vascularis (Ito et al, 2015). …”

Stria vascularis and cochlear hair cell changes in syphilis: A human temporal bone study

“…Degeneration of the stria vascularis has also been reported as a possible cause of progressive sensorineural hearing loss [21]. As the main producer of endolymph, the stria vascularis is expected to be affected in otosyphilis.…”