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Postsynaptic GluA3 subunits are required for the appropriate assembly of AMPA receptor GluA2 and GluA4 subunits on mammalian cochlear afferent synapses and for presynaptic ribbon modiolar-pillar morphological distinctions

The encoding of acoustic signals in the cochlea depends on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), but relatively little is known about their reliance on specific pore-forming subunits. With 5-week-old male GluA3KO mice, we determined cochlear function, synapse ultrastructure, and AMPAR subunit molecular anatomy at ribbon synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs). GluA3KO and wild-type (GluA3WT) mice reared in ambient sound pressure level (SPL) of 55-75 dB had similar ABR thresholds, wave-1 amplitudes, and latencies. Ultrastructurally, the IHC modiolar-pillar differences in presynaptic ribbon size and shape, and synaptic vesicle size seen in GluA3WT were diminished or reversed in GluA3KO. The quantity of paired synapses (presynaptic ribbons juxtaposed with postsynaptic GluA2 and GluA4) was similar, however, GluA2-lacking synapses (ribbons paired with GluA4 but not GluA2) were observed only in GluA3KO. SGNs of GluA3KO mice had AMPAR arrays of smaller overall volume, containing less GluA2 and greater GluA4 immunofluorescence intensity relative to GluA3WT (3-fold difference in mean GluA4:GluA2 ratio). The expected modiolar-pillar gradient in ribbon volume was observed in IHCs of GluA3WT but not GluA3KO. Unexpected modiolar-pillar gradients in GluA2 and GluA4 volume were present in GluA3KO. GluA3 is essential to the morphology and molecular composition of IHC-ribbon synapses. We propose the hearing loss seen in older male GluA3KO mice results from progressive synaptopathy evident in 5-week-old mice as increased abundance of GluA2-lacking, GluA4 monomeric, Ca2+-permeable AMPARs.