[HTML][HTML] Sex differences in glutamate AMPA receptor subunits mRNA with fast gating kinetics in the mouse cochlea

NR Lozier, S Muscio, I Pal, HM Cai… - Frontiers in Systems …, 2023 - frontiersin.org
NR Lozier, S Muscio, I Pal, HM Cai, ME Rubio
Frontiers in Systems Neuroscience, 2023frontiersin.org
Evidence shows that females have increased supra-threshold peripheral auditory
processing compared to males. This is indicated by larger auditory brainstem responses
(ABR) wave I amplitude, which measures afferent spiral ganglion neuron (SGN)-auditory
nerve synchrony. However, the underlying molecular mechanisms of this sex difference are
mostly unknown. We sought to elucidate sex differences in ABR wave I amplitude by
examining molecular markers known to affect synaptic transmission kinetics. Alpha-amino-3 …
Evidence shows that females have increased supra-threshold peripheral auditory processing compared to males. This is indicated by larger auditory brainstem responses (ABR) wave I amplitude, which measures afferent spiral ganglion neuron (SGN)-auditory nerve synchrony. However, the underlying molecular mechanisms of this sex difference are mostly unknown. We sought to elucidate sex differences in ABR wave I amplitude by examining molecular markers known to affect synaptic transmission kinetics. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate fast excitatory transmission in mature SGN afferent synapses. Each AMPAR channel is a tetramer composed of GluA2, 3, and 4 subunits (Gria2, 3, and 4 genes), and those lacking GluA2 subunits have larger currents, are calcium-permeable, and have faster gating kinetics. Moreover, alternatively spliced flip and flop isoforms of each AMPAR subunit affect channel kinetics, having faster kinetics, those AMPARs containing Gria3 and Gria4 flop isoforms. We hypothesized that SGNs of females have more fast-gating AMPAR subunit mRNA than males, which could contribute to more temporally precise synaptic transmission and increased SGN synchrony. Our data show that the index of Gria3 relative to Gria2 transcripts on SGN was higher in females than males (females: 48%; males: 43%), suggesting that females have more SGNs with higher Gria3 mRNA relative to Gria2. Analysis of the relative abundance of the flip and flop alternatively spliced isoforms showed that females have a 2-fold increase in fast-gating Gria3 flop mRNA, while males have more slow-gating (2.5-fold) of the flip. We propose that Gria3 may in part mediate greater SGN synchrony in females.
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