This research will identify fundamental mechanisms by which environmental toxicants produce cochlear dysfunction and injury. This will improve prediction of ototoxic chemicals and instances where environmental contaminants potentiate the damaging effect of noise on hearing. Two central hypotheses drive this research. The first hypothesis states that the initial synapse in the auditory system formed by the inner hair cell (IHC) and Type 1 spiral ganglion cell (SGC1) is vulnerable to glutamate excitotoxicity. This hypothesis will be tested by measuring changes in spontaneous and sound-elicited firing rates of auditory nerve units following trimethyltin (TMT) and by assessing whether glutamate receptor antagonists protect against synaptic dysfunction and post-synaptic injury. Sub-hypotheses, that the excessive release of glutamate from the IHC is dependent on increased extracellular Ca++ uptake and that SGC1 dysfunction results from elevated Ca++ will be tested by determining cytosolic Ca++ levels using Ca++ sensitive fluorescent dyes, determining the source of the Ca++ elevation, and whether Ca++ channel antagonists can protect against TMT dysfunction. The second hypothesis states that elevated Ca++ levels within the outer hair cell (OHC) are responsible for dysfunction and injury observed following TMT. This hypothesis will be tested by establishing that TMT's effects at the OHC are independent of its excitotoxic action and then by relating the elevation in cytosolic Ca++ with subsequent disruption of OHC shape. Ca++ sensitive dyes will be used to assess cytosolic Ca++ levels. TMT will be used as a model compound to test these hypotheses because data from the central nervous system implicate excitotoxicity and enhanced cytosolic Ca++ levels in its neurotoxicity. While several other environmental chemicals are also important excitotoxic candidates, TMT has well established toxic effects in the cochlea at the two different targets. Further TMT provokes a very rapid toxic action in the cochlea at a dose level approximately a full order of magnitude lower than that used to detect CNS dysfunction and pathology.
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