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(American Journal of Pathology. 2006;169:528-543.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060122

Aminoglycoside-Induced Degeneration of Adult Spiral Ganglion Neurons Involves Differential Modulation of Tyrosine Kinase B and p75 Neurotrophin Receptor Signaling

Justin Tan*{dagger} and Robert K. Shepherd*{dagger}

From The Bionic Ear Institute, East Melbourne*; and the Department of Otolaryngology,{dagger} University of Melbourne, East Melbourne, Victoria, Australia

Aminoglycoside antibiotics induce sensorineural hearing loss by destroying hair cells of the organ of Corti, causing progressive secondary degeneration of primary auditory or spiral ganglion neurons (SGNs). Recent studies show that the p75 neurotrophin receptor (NTR) is aberrantly up-regulated under pathological conditions when the neurotrophin receptor tyrosine kinases (Trks) are presumptively down-regulated. We provide in vivo evidence demonstrating that degenerating SGNs induced an augmented p75NTR expression and a coincident reduction of TrkB expression in their peripheral processes. Nuclear transcription factors c-Jun and cyclic AMP response element-binding protein phosphorylated by p75NTR- and TrkB-activated signal pathways, respectively, also showed a corresponding differential modulation, suggesting an activation of apoptotic pathways, coupled to a loss of pro-survival neurotrophic support. Our findings identified brain-derived neurotrophic factor (BDNF) expression in hair and supporting cells of the adult cochlea, and its loss, specifically the mature form, would impair TrkB-induced signaling. The precursor of BDNF (pro-BDNF) is differentially cleaved in aminoglycoside-deafened cochleae, resulting in a predominant up-regulation of a truncated form of pro-BDNF, which colocalized with p75NTR-expressing SGN fibers. Together, these data suggest that an antagonistic interplay of p75NTR and TrkB receptor signaling, possibly modulated by selective BDNF processing, mediates SGN death in vivo.




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J. Tan, S. Widjaja, J. Xu, and R. K. Shepherd
Cochlear Implants Stimulate Activity-Dependent CREB Pathway in the Deaf Auditory Cortex: Implications for Molecular Plasticity Induced by Neural Prosthetic Devices
Cereb Cortex, August 1, 2008; 18(8): 1799 - 1813.
[Abstract] [Full Text] [PDF]


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