Female GluA3-KO mice show early onset hearing loss and afferent swellings in ambient sound levels

Abstract

AMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3^KO) in male mice reduced cochlear output by 8-weeks of age. Since Gria3 is X-linked and considering sex differences in hearing vulnerability, we hypothesized accelerated presbycusis in Gria3^KO females. Here, auditory brainstem responses (ABR) were similar in 3-week-old female Gria3^WT and Gria3^KO mice. However, when raised in ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-weeks and older in Gria3^KO. In contrast, these metrics were similar between genotypes when raised in quiet. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were increased in female Gria3^KO mice in ambient sound compared to Gria3^WT or to either genotype raised in quiet. Synaptic GluA4:GluA2 ratios increased relative to Gria3^WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in Gria3^KO. Swollen afferent terminals were observed by 5-weeks only in Gria3^KO females reared in ambient sound. We propose that lack of GluA3 induces sex-dependent vulnerability to AMPAR-mediated excitotoxicity.

Keywords: 3D reconstructions; AMPA receptors; Gria3; auditory nerve fibers; confocal immunofluorescence; hearing loss; inner hair cells; molecular anatomy; ribbon synapses; ultrastructure.