The Medial Olivocochlear System Modulates the Development of the Auditory Pathway

CASTAGNA VC, BOERO LE, DI GUILMI MN, FUCHS P, ELGOYHEN AB AND GOMEZ-CASATI ME

CONFERENCIA VIRTUAL

Congreso; 44rd ARO meeting.; 2021

Association for Research in Otolaryngology

Patterned spontaneous activity is a hallmark of developing sensory systems. Cochlear inner haircells (IHCs) of altricial mammals display spontaneous electrical activity before the onset ofhearing. It has been suggested that the pattern and firing rate of these cells and theirpostsynaptic afferent partners are crucial for the correct maturation of the central auditorypathway. During this developmental window, a descending medial efferent innervation from thecentral nervous system makes direct synaptic contacts with IHCs and modulates thisspontaneous activity. In this work we try to understand the function of this transient efferentsynapse during the critical period and show that genetic enhancement or ablation of medialolivocochlear (MOC) function alters cochlear development.We used genetically modified mice with different levels of α9α10 nAChR activity: an α9 nicotinicreceptor subunit knock-out (Chrna9 KO) which lacks cholinergic transmission between efferentneurons and hair cells, and a gain of function knock-in (Chrna9L9?T KI) carrying an α9 pointmutation that leads to enhanced MOC activity.First, we tracked the onset of the auditory brainstem responses (ABR) in wild type (WT), Chrna9KO(KO) and Chrna9L9 ́T KI (KI) mice. ABR measurements were obtained daily in anesthetizedmice between postnatal day 12 (P12) and P21. Also, we queried which are the consequences ofan early exposure to acoustic trauma, for that we exposed P15 WT animals to acoustic traumafor one hour at 110 dB and evaluated the ABR measures 1 and 7 days after.We found that ABR onset was earlier in KI mice, with enhanced MOC function, compared to micewith normal MOC synapses. KI mice had a measurable ABR at P13 and reached mature thresholdlevels 1-2 days before their corresponding WT littermates. In contrast, ABR onset in KO ears wasdelayed, suggesting that cochlear maturation is slowed in the absence of pre-hearing efferentmodulation. We then analyzed the maximum response amplitude for ABR peak I, II and III atdifferent postnatal ages in the three genotypes. At P16, when the auditory thresholds reachedsimilar levels in all three genotypes, peak I amplitudes were not different from amplitudes atP21. However, at P16 peaks II and III differ from their amplitudes at P21 in all three genotypes,suggesting that the maturation of the central connections begins in the periphery and continuesafter the onset of hearing.These results show that auditory sensitivity in mice with enhanced or null MOC activity is alteredat hearing onset. Thus, our work adds to the notion that the transient efferent innervation tothe cochlea is necessary for the correct establishment of the auditory circuitry and thatdisruption of spontaneous activity patterns could modify peripheral and central components ofauditory development. In addition our results show that the exposure to acoustic trauma at earlystages can alter the maturation of the auditory system.