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

Abstract

Hearing loss is one of the most common disabilities in modern society and is exacerbated by aging and our extensive exposure to loud noise or ototoxic drugs such as aminoglycoside antibiotics.¹ In most cases, the hearing impairment results from damage to the cochlear sensory hair cells of the inner ear. Because mammalian hair cells are incapable of regeneration, their loss inevitably and irreversibly causes hearing loss.² Sensory hair and supporting cells in the organ of Corti provide neurotrophic support to primary auditory (spiral ganglion) neurons,^3–5 and their loss can trigger a secondary degeneration of these neurons.^6–8

Spiral ganglion neurons (SGNs) express the neurotrophin receptors tropomyosin-related kinase (Trk) receptor tyrosine kinase and the p75 neurotrophin receptor (NTR), a member of the tumor necrosis factor receptor superfamily.^9,10 The Trk receptors bind different members of the neurotrophin family, with TrkA showing a preference for nerve growth factor, TrkB selectively binding brain-derived neurotrophic factor (BDNF) and neurotrophin 4/5, and TrkC preferentially interacting with neurotrophin 3 (NT-3).¹¹ The p75NTR, however, can bind all neurotrophins and also interacts with Trk receptors to modulate ligand binding specificity, affinity, and functionality within certain cell types.^12,13 TrkA is not known to be present in SGNs as assessed by both immunohistochemical and in situ hybridization analyses,^10,14 whereas TrkB, TrkC, and p75NTR mRNAs have been detected in SGNs.^9,10 Studies of mutant mice with deletions in TrkB and TrkC reveal significant loss of SGNs and innervation defects in the cochlea during development,¹⁵ whereas adult mutant mice with severely reduced TrkB signaling have been associated with a significant hearing loss.¹⁶

At least two signaling pathways, notably the phosphoinositide 3-kinase and the mitogen-activated protein kinase cascades, mediate Trk-activated survival response in neurons.^17,18 In contrast, the role of p75NTR in the cochlea remains elusive, but it has been suggested to play a role in the formation of the inner sulcus during cochlear development, presumptively through apoptotic events and the differentiation of Pillar cells to form the tunnel of Corti.^9,19 Recently, p75NTR has been shown to be aberrantly up-regulated under pathological and inflammatory conditions,^20–22 when Trk receptors may have been presumptively down-regulated, suggesting that an imbalance of neurotrophin receptor signaling may be involved in diseases of the nervous system.²³ Furthermore, certain precursors of neurotrophins (pro-neurotrophins) have been shown to mediate cell apoptosis by binding to p75NTR.^24–26

Because p75NTR and Trk receptors are frequently coexpressed in the same neuron, we sought to establish to what extent each individual receptor is associated with neuronal death in degenerating SGNs using an in vivo model, relevant to deafness-induced pathological changes in the cochlea. We used aminoglycoside antibiotics to destroy sensory hair and supporting cells in the organ of Corti of rats and analyzed the expression of these neurotrophin receptors in SGNs after a deafness period ranging from 6 weeks to 4 months. The data show an augmentation of p75NTR expression and a reduced TrkB expression in degenerating SGNs, concomitant with a temporal decline of SGN density in the Rosenthal’s canal where these molecular changes occur. Coincidentally, the proportion of degenerating neurons expressing phosphorylated c-Jun, a target of p75NTR-mediated pathway,^27,28 is increased, whereas there is a converse decline in the proportion of neurons expressing phosphorylated cyclic AMP response element binding protein (CREB), a target of TrkB-mediated pathway.²⁹ Our studies also identify an elevation of a truncated form of pro-BDNF and a reduction of mature BDNF in amino-glycoside-deafened cochleae, reflecting a differential processing of BDNF under pathological conditions. These findings not only provide insights into the antagonistic interplay of p75NTR and TrkB receptor signaling as a key event in SGN degeneration, but they also have general implications in the design of pharmacological agents to target specific growth factor signaling pathway to ameliorate deafness.

Acknowledgments

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