Aminoglycoside-Induced Otoneurotoxicity: Analysis of Inner Hair Cell Synaptic Plasticity Following Drug Exposure

Aminoglycoside antibiotics are powerful drugs for combating bacterial infections, but are limited in use due to their ototoxicity. This class of drug targets the auditory hair cells of the cochlea, causing cell death, which leads to a decline in auditory function. In spite of much research aimed at revealing a mechanism of damage, there are no co-therapies available to diminish the ototoxic liability of aminoglycosides. Existing research does show that there may be a neurodegenerative process that contributes to the observed toxicity. In an effort towards clarifying present understanding of issue, this dissertation project was conducted to characterize the neurodegenerative effects of kanamycin, a commonly used aminoglycoside antibiotic. Specifically we assessed the effects of kanamycin on inner hair cell ribbon synapse degeneration and plasticity in the guinea pig. The project first identified the drug concentration and number of doses necessary to induce the desired effect, loss of inner hair cell ribbons. The kanamycin dosing regimen employed produced significant high frequency hearing loss with associated outer hair cell loss 14 days following the last administration. Although there was no inner hair cell loss at this time, treatment caused significant decreases in inner hair cell ribbons in the furthest basal regions of the cochlea. The next phase of the project examined how ribbon densities changed over time following kanamycin administration. Here, results demonstrated that doses of kanamycin administered for 10 consecutive days generated significant reductions in ribbon densities acutely, followed thereafter by ribbon regeneration. The hearing deficits and outer hair cell losses, in addition the severity of the ribbon density changes were more severe with the increased dosage. Interestingly, the postsynaptic spiral ganglion neurons were not affected at 56 days from the last dose. The next project specifically looked at how kanamycin affected the inner hair cell ribbon and associated postsynaptic glutamate receptors. The results showed similar synaptic loss following dosing and confirmed that synaptic regeneration occurs over time. The final experiment in this series looked at how intra-aural gentamicin affects synapse densities acutely. The results indicate that intra-aural administration produces greater synaptic losses throughout the cochlea as compared to systemic administration. In conclusion, this project established the role of synaptopathic effects of aminoglycoside ototoxicity, and additionally illustrated the capacity for regeneration following the initial expression of such ototoxicity. ii ACKNOWLEDGMENTS I would like to thank everyone who has helped mentor and support me through my graduate career. I would like to …