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

Abstract

AbstractAMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3KO) in male mice reduced cochlear output by 8-weeks of age. SinceGria3is X-linked and considering sex differences in hearing vulnerability, we hypothesized accelerated presbycusis inGria3KOfemales. Here, auditory brainstem responses (ABR) were similar in 3-week-old femaleGria3WTandGria3KOmice. However, when raised in ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-weeks and older inGria3KO. 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 femaleGria3KOmice in ambient sound compared toGria3WTor to either genotype raised in quiet. Synaptic GluA4:GluA2 ratios increased relative toGria3WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs inGria3KO. Swollen afferent terminals were observed by 5-weeks only inGria3KOfemales reared in ambient sound. We propose that lack of GluA3 induces sex-dependent vulnerability to AMPAR-mediated excitotoxicity.