Medial Olivocochlear Activity Modulates Central Auditory Synapse Structure and Function

Abstract In many mammals, the auditory system is immature at birth and undergoes activity-dependent refinement. The medial olivocochlear system (MOC) contributes to the maturation of central auditory connectivity by shaping spontaneous activity in the developing inner ear. Although altered MOC activity has been linked to electrical and synaptic dysfunctions in different central auditory nuclei, an in-depth analysis of the same synapse under conditions of absent versus enhanced MOC activity is lacking. In this work, we set out a physiological and structural analysis of the calyx of Held and the principal neurons of the medial nucleus of the trapezoid body (CH-MNTB) synapse at postnatal days 12-14 in three mouse models of either sex: wild-type (WT), α9 knock-in (α9KI; with enhanced MOC activity), and α9 knock-out (α9KO; which lacks MOC activity). Electrophysiological recordings in brain slices revealed a reduced synaptic strength efficacy in α9KI compared to WT, including smaller excitatory postsynaptic current (EPSC) amplitudes, stronger short-term depression during repetitive stimulation and a decrease readily releasable pool size. In contrast, α9KO mice showed minimal synaptic differences relative to WT. Serial block-face electron microscopy (SBEM) reconstructions demonstrated morphological alterations of the CH in both MOC-manipulated mouse models. However, α9KI mice exhibited the largest deviations, including fewer morphologically complex CHs and increased poly-innervation of MNTB cells. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Moreover, the enhancement of MOC activity drives more pronounced developmental changes in brainstem auditory circuitry than its absence. Significance Statement Before hearing onset, inner hair cells in altricial mammals show spontaneous electrical activity crucial for proper auditory pathway development. This activity is finely regulated by descending efferent nerves from the central nervous system during a critical developmental period, ensuring precise auditory circuit formation. Our study shows that genetically manipulating efferent function —either by eliminating it or enhancing it— leads to structural alterations and severe synaptic dysfunction within the auditory brainstem. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Importantly, enhancing efferent peripheral activity causes more pronounced central synaptic changes than its absence, highlighting the importance of balanced efferent modulation during early auditory system development for normal brainstem auditory function. Competing Interest Statement The authors have declared no competing interest.