Autophagy-Mediated Synaptic Refinement and Auditory Neural Pruning Contribute to Ribbon Synaptic Maturity in the Developing Cochlea.

Rui Guo,Wei Xiong,Zhengde Du,Zezhang Tao,Ke Liu,Yice Xu,Yue Qi,Shusheng Gong,Wei Wei

doi:10.3389/fnmol.2022.850035

Abstract

In rodents, massive initial synapses are formed in the auditory peripheral nervous system at the early postnatal stage, and one of the major phenomena is that the number of afferent synapses in the cochlea is significantly reduced in the duration of development. This raises the hypothesis that the number of cochlear ribbon synapses are dramatically changed with hearing development and maturation. In this study, several tracers identifying activities of autophagy were applied to estimate the level of autophagy activity in the process of ribbon synapse development in mice; further, changes in the synaptic number and spiral ganglion nerve (SGN) fibers were quantitatively measured. We found robust expression of LC3B and lysosomal-associated membrane protein 1 as well as LysoTracker in or near inner hair cells and cochlear ribbon synapses in the early stage of postnatal development. Moreover, we found a significant loss in the intensity of SGN fibers at ribbon synaptic development and hearing onset. Thus, this study demonstrates that ribbon synaptic refinement and SGN fibers pruning are closely associated with the morphological and functional maturation of ribbon synapses and that synaptic refinement and SGN fiber pruning are regulated by the robust activities of autophagy in the earlier stages of auditory development.

Highlights

Acoustic signals are sensed by cochlear hair cells and transmit information to the central nervous system via the spiral ganglion neurons (SGNs) (Liu et al, 2019; Wei et al, 2021)
Because the amplitude of the auditory brainstem response (ABR) wave I has been demonstrated to roughly reflect the function of cochlear ribbon synapses (Qi et al, 2019; Xiong et al, 2020b), we estimated the changes in the amplitude of the ABR wave I and found a significantly increased amplitude of the ABR wave I at P28 at 4, 8, and 32 kHz compared with that at P14 (Figures 1a,b,D)
Our findings showed that there may be a dramatic loss in the number of cochlear ribbon synapses during auditory development and maturation

Summary

Introduction

Acoustic signals are sensed by cochlear hair cells and transmit information to the central nervous system via the spiral ganglion neurons (SGNs) (Liu et al, 2019; Wei et al, 2021) In mammals, this task is accomplished by using several synaptic structures with special features along the hearing pathway (Raphael and Altschuler, 2003; Wichmann and Moser, 2015). Our previous study showed that autophagy is required for the remodeling of cochlear ribbon synapses in postnatal mice (Xiong et al, 2020a) Despite this evidence, synaptic refinement and SGN fiber pruning have not yet been fully explored; it is still unclear whether synaptic refinement and SGN fiber pruning are fully mediated via dynamic autophagy flux (Ding et al, 2020; Zhou et al, 2020; Fu et al, 2021; Guo et al, 2021). Our study showed that quantitative reduction and functional facilitation of ribbon synapses, as well as density loss of SGN fibers, are regulated by dynamic autophagy flux, suggesting that both ribbon synaptic refinement and auditory neural fiber pruning are regulated via the dynamic activities of autophagy, which plays a key role in the development and construction of cochlear ribbon synapses

Methods

Results

Conclusion