An antibody to RGMa promotes regeneration of cochlear synapses after noise exposure

Jerome Nevoux,Yushi Hayashi,Kohsuke Tani,Hanae Lahlou,Albert S. B. Edge,Thomas Bellocq,Lei Tanaka,Takahisa Watabe,Mihaela Alexandru

doi:10.1038/s41598-021-81294-5

Abstract

Auditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion. Recent work has identified the synapse between cochlear primary afferent neurons and sensory hair cells as a particularly vulnerable component of this pathway. Loss of these synapses due to noise exposure or aging results in the pathology identified as hidden hearing loss, an initial stage of cochlear dysfunction that goes undetected in standard hearing tests. We show here that repulsive axonal guidance molecule a (RGMa) acts to prevent regrowth and synaptogenesis of peripheral auditory nerve fibers with inner hair cells. Treatment of noise-exposed animals with an anti-RGMa blocking antibody regenerated inner hair cell synapses and resulted in recovery of wave-I amplitude of the auditory brainstem response, indicating effective reversal of synaptopathy.

Highlights

Auditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion
RNAscope showed that repulsive axonal guidance molecule a (RGMa) mRNA was present in supporting cells that surround the nerve endings, suggesting that the protein was made in supporting cells where it could be retained at the membrane or released to bind to its receptor on neurons (Fig. 1B)
Both proteins are present at the synapse and their expression pattern suggests that RGMa at the surface of supporting cells or in the extracellular space could bind to neogenin[1] to repulse spiral ganglion neural growth cones at the inner hair cells

Summary

Introduction

Auditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion. Treatment of noise-exposed animals with an anti-RGMa blocking antibody regenerated inner hair cell synapses and resulted in recovery of wave-I amplitude of the auditory brainstem response, indicating effective reversal of synaptopathy. RGMs bind the type 1 transmembrane protein neogenin[1], which controls axon guidance and neuronal survival effects. In previous studies we found that an antibody against RGMa increased the innervation of postnatal organ of Corti by spiral ganglion neurons[8] These experiments were performed as an in vitro model for the replacement of auditory neurons by embryonic stem cells in an attempt to devise stem cell-based treatments for auditory neuropathy[9,10,11], the loss of auditory neurons that occurs in genetic diseases as well as age and noise related insults to the cochlea

Methods

Results

Conclusion