Cochlear Amplification Modulates Synaptic Transmission at the Endbulb of Held Synapse in the Cochlear Nucleus

In the mammalian cochlea upon acoustic stimulation, outer hair cells (OHCs) push and pull the basilar membrane, amplifying its vibration and therefore expanding the dynamic range of hearing. As a result, spiking patterns in auditory nerve fibers (ANFs) are believed to be significantly different, but how the central nervous system adapts to this substantial change is poorly understood. In this study, we took advantage of Prestin -/- mice of either sex where prestin, the motor protein in OHCs, was genetically knocked out, therefore removing cochlear amplification completely without changing the cellular structure of the cochlea significantly. While exocytosis from inner hair cells in the cochlea was largely intact, transmission at the endbulb of Held synapse between ANFs and bushy cells in the cochlear nucleus was significantly changed in Prestin -/- mice. Specifically, excitability of bushy cells was significantly increased, due to combination of slightly more depolarized resting membrane potential, increased membrane input resistance, and smaller and briefer after-hyperpolarization. Furthermore, synaptic strength was greatly reduced, caused by substantial decrease in the readily releasable pool (RRP) of synaptic vesicles. Significantly, paired-pulse plasticity at this synapse was reversed from depression in WT mice to facilitation in Prestin -/- mice, likely caused by quicker refilling of RRP observed in Prestin -/- mice. In conclusion, we found that transmission at the endbulb of Held synapse is significantly altered in absence of cochlear amplification, revealing interplay between the peripheral and central processing of auditory signals that contributes to expanded dynamic range of hearing seen in mammals and humans. Significance Statement The mammalian cochlea is an amazing sensory apparatus with remarkable sensitivity, largely owning to cochlear amplification that is estimated to be ∼1,000 folds. As a result, auditory nerve fibers are expected to fire spikes with significantly different patterns. If and how central circuits adapt to this substantial change of cochlear input are poorly understood. To address this fundamental question, we abolished cochlear amplification in Prestin -/- mice and examined functional changes in the cochlear nucleus. We found that excitability of bushy cells was increased, and transmission at the endbulb of Held synapse was significantly altered. We therefore revealed an active interaction between the hearing organ and central circuits that expands our understanding of hearing in general.