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bioRxiv · 10.1101/433581

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

Di Guilmi, M. N.·Boero, L. E.·Castagna, V. C.·Rodriguez-Contreras, A.·Wedemeyer, C.·Gomez-Casati, M. E.·Elgoyhen, A. B.
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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 9 cholinergic receptor knock-in mouse model (of either sex) with enhanced medial efferent activity (Chrna9L9T, L9T) 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 L9T 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 L9T 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.\n\nSignificance 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.

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Di Guilmi, M. N., Boero, L. E., Castagna, V. C., Rodriguez-Contreras, A., Wedemeyer, C., Gomez-Casati, M. E., Elgoyhen, A. B.. 2018-10-02. Strengthening of the efferent olivocochlear system leads to synaptic dysfunction and tonotopy disruption of a central auditory nucleus. https://doi.org/10.1101/433581

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