Acoustic trauma slows AMPAR-mediated EPSCs in the auditory brainstem reducing GluA4 subunit expression as a mechanism to rescue binaural function

Key points

• LSO principal neurons receive AMPAR & NMDAR-mediated EPSCs and glycinergic IPSCs.
• Both EPSCs and IPSCs have slow kinetics in prehearing animals, which on maturation accelerate to sub-millisecond decay time-constant. This correlates with glutamate and glycine receptor subunit mRNA levels.
• The NMDAR-EPSCs accelerate over development to achieve decay time-constants of 2.5 ms. This is the fastest NMDAR-mediated EPSC reported.
• Loud sounds slow AMPAR-EPSC decay, increasing GluA1 and decreasing GluA4 mRNA.
• Modelling of Interaural Intensity Difference suggests that the increased EPSC duration after AT shifts IID to the right and compensates for hearing loss.
• Two months after AT the EPSC decay times had recovered to control values.
• Synaptic transmission in the LSO matures by P20, with EPSCs and IPSCs having fast kinetics. AT changes the AMPAR subunits expressed and slows the EPSC time-course at synapses in the central auditory system.

Abstract

Damaging levels of sound (acoustic trauma, AT) diminish peripheral synapses, but what is the impact on the central auditory pathway? Developmental maturation of synaptic function and hearing were characterized in the mouse lateral superior olive (LSO) from P7 to P96 using voltage-clamp and auditory brainstem responses (ABR). IPSCs and EPSCs show rapid acceleration during development, so that decay kinetics converge to similar sub-millisecond time-constants (τ, 0.87 ± 0.11 ms, 0.77 ± 0.08 ms, respectively) in adult mice. This correlated with LSO mRNA levels for glycinergic and glutamatergic ionotropic receptor subunits; confirming a switch from Glyα2 to Glyα1 for IPSCs and increased expression of GluA3 and GluA4 subunits for EPSCs. The NMDAR-EPSC decay τ accelerated from > 40 ms in prehearing animals, to 2.6 ± 0.4 ms in adults, as GluN2C expression increased. In vivo induction of AT at around P20, disrupted IPSC and EPSC integration in the LSO, so that one week later the AMPAR-EPSC decay was slowed and mRNA for GluA1 increased while GluA4 decreased. In contrast, GlyR IPSC and NMDAR-EPSC decay times were unchanged. Computational modelling confirmed that matched IPSC and EPSC kinetics are required to generate mature interaural level difference (IID) functions, and that longer-lasting EPSCs compensates to maintain binaural function with raised auditory thresholds after AT. We conclude that LSO excitatory and inhibitory synaptic drive matures to identical time-courses; that AT changes synaptic AMPARs by expression of subunits with slow kinetics (which recover over two months) and that loud sounds reversibly modify excitatory synapses in the brain, changing synaptic function for several weeks after exposure.

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