Strengthening of the efferent olivocochlear system leads to synaptic dysfunction and tonotopy disruption of a central auditory nucleus

Abstract

The auditory system in many mammals is immature at birth but precisely organized in adults. Spontaneous activity in the inner ear plays a critical role in guiding this process. This is shaped by an efferent pathway that descends from the brainstem and makes transient direct synaptic contacts with inner hair cells (IHCs). In this work, we used an α9 cholinergic receptor knock-in mouse model (of either sex) with enhanced medial efferent activity (Chrna9L9’T, L9’T) to understand the role of the olivocochlear system in the correct establishment of auditory circuits. Wave III of auditory brainstem responses (which represents synchronized activity of synapses within the superior olivary complex) were smaller in L9’T mice, suggesting a central dysfunction. The mechanism underlying this functional alteration was analysed in brain slices containing the medial nucleus of the trapezoid body (MNTB), where neurons are topographically organized along a medio-lateral axis. The topographic organization of MNTB physiological properties observed in WT mice was abolished in the L9’T mice. Additionally, electrophysiological recordings in slices evidenced MNTB synaptic alterations, which were further supported by morphological alterations. The present results suggest that the transient cochlear efferent innervation to IHCs during the critical period before the onset of hearing is involved in the refinement of topographic maps as well as in setting the correct synaptic transmission at central auditory nuclei.Significance StatementCochlear inner hair cells of altricial mammals display spontaneous electrical activity before hearing onset. The pattern and firing rate of these cells is crucial for the correct maturation of the central auditory pathway. A descending efferent innervation from the central nervous system contacts hair cells during this developmental window. The function of this transient efferent innervation remains an open question. The present work shows that the genetic enhancement of efferent function disrupts the orderly topographic distribution at the medial nucleus of the trapezoid body level and causes severe synaptic dysfunction. Thus, the transient efferent innervation to the cochlea is necessary for the correct establishment of the central auditory circuitry.

Efferent feedback enforces bilateral coupling of spontaneous activity in the developing auditory system

“…Thresholds determined with the only visible ABR waves I-II are largely normal in the α9 nAChR knockouts compared to controls ( Figure 5A-B), consistent with data from adults (Morley et al, 2017). Our results suggest that central circuits downstream to the CN, rather than the peripheral machinery, are undermined in the knockout, which are in line with previous reports of impaired tonotopic refinement and synaptic functions in the MNTB with either the α9 nAChR knockout (Clause et al, 2014) or the enhanced α9 nAChR knock-in (Di Guilmi et al, 2019). However, more indepth investigation on the intactness of the sensory periphery is needed for a more definitive conclusion.…”

“…Finally, we also observed elevated auditory thresholds in the α9/α10 nAChR knockout mice immediately after hearing onset, based on calcium responses in the IC ( Figure 5). Our results, combined with the existing literature (Clause et al, 2014, Clause et al, 2017, Di Guilmi et al, 2019, demonstrate that disruptions of spontaneous activity patterns could undermine different aspects of auditory development.…”

Efferent feedback controls bilateral auditory spontaneous activity

“…5). Our results, combined with the existing literature 24,31,32 , demonstrate that disrupting spontaneous activity patterns undermines the normal development of auditory circuits.…”

Purinergic signaling controls spontaneous activity in the auditory system throughout early development

“…However, auditory brainstem neurons in (anesthetized) α9 KO mice exhibit prominent burst firing in vivo, with bursts occurring at similar frequencies, but with shorter durations and containing more action potentials than controls (Clause et al, 2014). Moreover, α9 GOF mice that have enhanced efferent inhibition of IHCs (Wedemeyer et al, 2018), also exhibit spontaneous action potentials in the auditory brainstem, although at lower frequencies than controls (Di Guilmi et al, 2019). Our in vivo macroscopic imaging studies indicate that periodic excitation of auditory midbrain neurons occurred in α9 KO mice at the same frequency as controls (Figure 11), reinforcing the conclusion that efferent input is not required to initiate burst firing.…”