Age-Dependency of Neurite Outgrowth in Postnatal Mouse Cochlear Spiral Ganglion Explants.

Claudia Frick,Karl-Heinz Wiesmüller,Marcus Müller,Dominik Schmidbauer,Hubert Löwenheim,Francis Rousset,Anke Tropitzsch,Holger Eickhoff,Helge Rask-Andersen,Pascal Senn,Stefan Fink,Rudolf Glueckert,Benedikt Kramer

doi:10.3390/brainsci10090580

Abstract

Background: The spatial gap between cochlear implants (CIs) and the auditory nerve limits frequency selectivity as large populations of spiral ganglion neurons (SGNs) are electrically stimulated synchronously. To improve CI performance, a possible strategy is to promote neurite outgrowth toward the CI, thereby allowing a discrete stimulation of small SGN subpopulations. Brain-derived neurotrophic factor (BDNF) is effective to stimulate neurite outgrowth from SGNs. Method: TrkB (tropomyosin receptor kinase B) agonists, BDNF, and five known small-molecule BDNF mimetics were tested for their efficacy in stimulating neurite outgrowth in postnatal SGN explants. To modulate Trk receptor-mediated effects, TrkB and TrkC ligands were scavenged by an excess of recombinant receptor proteins. The pan-Trk inhibitor K252a was used to block Trk receptor actions. Results: THF (7,8,3′-trihydroxyflavone) partly reproduced the BDNF effect in postnatal day 7 (P7) mouse cochlear spiral ganglion explants (SGEs), but failed to show effectiveness in P4 SGEs. During the same postnatal period, spontaneous and BDNF-stimulated neurite outgrowth increased. The increased neurite outgrowth in P7 SGEs was not caused by the TrkB/TrkC ligands, BDNF and neurotrophin-3 (NT-3). Conclusions: The age-dependency of induction of neurite outgrowth in SGEs was very likely dependent on presently unidentified factors and/or molecular mechanisms which may also be decisive for the age-dependent efficacy of the small-molecule TrkB receptor agonist THF.

Highlights

Cochlear implants (CIs), which are surgically placed into the cochlea, bypass damaged structures in the inner ear by directly stimulating the auditory nerve
As Brain-derived neurotrophic factor (BDNF) and NT-3 are differentially expressed in spiral ganglion neurons (SGNs) themselves [33,34], we investigated differences in spontaneous neurite outgrowth in spiral ganglion explants (SGEs) from P3, P4, P5, P6, and postnatal day 7 (P7) mouse cochlea
Age-dependent differences in spontaneous neurite outgrowth were investigated in P3, P4, P5, P6, and P7 SGEs cultured in medium devoid of neurotrophic supplements

Summary

Introduction

Cochlear implants (CIs), which are surgically placed into the cochlea, bypass damaged structures in the inner ear by directly stimulating the auditory nerve. Due to a spatial gap between spiral ganglion neurons (SGNs) of the auditory nerve and the CI electrodes, which mostly lie along the outer wall of the scala tympani [1,2,3], CI performance is limited by a broad spread of electrical charge [4] that limits frequency selectivity. Eliminating this spatial gap by promoting SGN survival and fiber growth toward and onto the CI electrode array is a generally accepted strategy for the improvement of CI performance (for review, see [5]). To improve CI performance, a possible strategy is to promote neurite outgrowth toward the CI, thereby allowing a discrete stimulation of small SGN subpopulations.

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Conclusion