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

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.