BDNF, NT-3 and Trk receptor agonist monoclonal antibodies promote neuron survival, neurite extension, and synapse restoration in rat cochlea ex vivo models relevant for hidden hearing loss.

Stephanie Szobota,Kristenann Black,Alan C Foster,Pranav D Mathur,Sairey Siegel,H Uri Saragovi,Michal Hetman

doi:10.1371/journal.pone.0224022

Stephanie Szobota, Kristenann Black + Show 5 more

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https://doi.org/10.1371/journal.pone.0224022

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Abstract

Neurotrophins and their mimetics are potential treatments for hearing disorders because of their trophic effects on spiral ganglion neurons (SGNs) whose connections to hair cells may be compromised in many forms of hearing loss. Studies in noise or ototoxin-exposed animals have shown that local delivery of NT-3 or BDNF has beneficial effects on SGNs and hearing. We evaluated several TrkB or TrkC monoclonal antibody agonists and small molecules, along with BDNF and NT-3, in rat cochlea ex vivo models. The TrkB agonists BDNF and a monoclonal antibody, M3, had the greatest effects on SGN survival, neurite outgrowth and branching. In organotypic cochlear explants, BDNF and M3 enhanced synapse formation between SGNs and inner hair cells and restored these connections after excitotoxin-induced synaptopathy. Loss of these synapses has recently been implicated in hidden hearing loss, a condition characterized by difficulty hearing speech in the presence of background noise. The unique profile of M3 revealed here warrants further investigation, and the broad activity profile of BDNF observed underpins its continued development as a hearing loss therapeutic.

Highlights

Spiral ganglion neurons convey sensory information from the hair cells of the cochlea to the brain stem and are vulnerable to damage from noise, aging, and underlying genetic diseases
While the small molecules had no effect in our assays, all of the M-antibodies induced Trk receptor activation, and we show that BDNF, NT-3 and the TrkB monoclonal antibody agonist, M3, are capable of driving robust SGN survival, neurite extension, and synapse restoration in an ex vivo model using excitotoxic trauma
Activation of the TrkB and TrkC neurotrophin receptors has been proposed as a promising treatment to reverse cochlear synaptopathy, an injury to the synapses connecting inner hair cells and spiral ganglion neurons that is thought to cause speech-in-noise hearing difficulties in humans

Summary

Introduction

Spiral ganglion neurons convey sensory information from the hair cells of the cochlea to the brain stem and are vulnerable to damage from noise, aging, and underlying genetic diseases. In animal models of noise trauma, recent studies have shown that SGN cell bodies and central axons can persist for months to years after insult [1,2], while the peripheral fibers and synaptic contacts with hair cells are rapidly and progressively degenerated, presumably due to the sudden and excessive release of glutamate from the presynaptic ribbons of the hair cells during loud noise [3,4]. The Canadian Institutes of Health Research had no role in study design, data collection and analysis, decision to publish, or preparation of this manuscript

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