The medial olivocochlear system modulates the development of the auditory pathway

CASTAGNA, VC; BOERO, L; DI GUILMI, MN; FUCHS PA; ELGOYHEN, AB; GÓMEZ CASATI, ME

Congreso; 44RD ANNUAL MidWinter Meeting; 2021

Patterned spontaneous activity is a hallmark of developing sensory systems. Cochlearinner hair cells (IHCs) of altricial mammals display spontaneous electrical activity beforethe onset of hearing. It has been suggested that the pattern and firing rate of these cellsand their postsynaptic afferent partners are crucial for the correct maturation of the centralauditory pathway. During this developmental window, a descending medial efferentinnervation from the central nervous system makes direct synaptic contacts with IHCsand modulates this spontaneous activity. In this work we queried the function of thistransient efferent synapse during the critical period and show that genetic enhancementor ablation of medial olivocochlear (MOC) function alters cochlear development.We used genetically modified mice with different levels of α9α10 nAChR activity: an α9nicotinic receptor subunit knock-out (Chrna9 KO) which lacks cholinergic transmissionbetween efferent neurons and hair cells, and a gain of function knock-in (Chrna9L9?T KI)carrying an α9 point mutation that leads to enhanced MOC activity.First, we tracked the onset of the auditory brainstem responses (ABR) in wild type (WT),Chrna9 KO (KO) and Chrna9L9´T KI (KI) mice. ABR measurements were obtained dailyin anesthetized mice between postnatal day 12 (P12) and P21. We found that ABR onsetwas earlier in KI mice, with enhanced MOC function, compared to mice with normal MOCsynapses. KI mice had a measurable ABR at P13 and reached mature threshold levels1-2 days before their corresponding WT littermates. In contrast, ABR onset in KO earswas delayed, suggesting that cochlear maturation is slowed in the absence of pre-hearingefferent modulation. We then analyzed the maximum response amplitude for ABR peakI, II and III at different postnatal ages in the three genotypes. At P16, when the auditorythresholds reached similar levels in all three genotypes, peak I amplitudes were notdifferent from amplitudes at P21. However, at P16 peaks II and III differ from theiramplitudes at P21 in all three genotypes, suggesting that the maturation of the centralconnections begins in the periphery and continues after the onset of hearing.Distortion product otoacoustic emissions (DPOAE) responses showed the same trend asABR thresholds: KI mice DPOAEs began earlier and reached mature threshold levels 1-2 days before WT mice; while there was a delay in the emergence of distortion productsin KO ears.These results show that auditory sensitivity in mice with enhanced or null MOC activity isaltered at hearing onset. Thus, our work adds to the notion that the transient efferentinnervation to the cochlea is necessary for the correct establishment of the auditorycircuitry and that disruption of spontaneous activity patterns could modify peripheral andcentral components of auditory development.