Prevention of Noise Damage to Cochlear Synapses
[Technical Report, Annual Report]
University of Iowa
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Noise-induced synaptopathy is the result of excitotoxic trauma to cochlear synapses due to glutamate released from the hair cells. Excitotoxic trauma damages the postsynaptic cell by causing entry of Ca2 ions. We have identified the route of Ca2 entry as via Ca2 -permeable AMPA-type glutamate receptors CP-AMPARs. These are a subset of glutamate receptors that lack the GluA2 subunit. We showed that a selective blocker of CP-AMPARs the anandamide compound IEM-1460 is protective against excitotoxicity and noise-induced synaptopathy. For the latter result we perfused IEM-1460 directly into the cochlea. In this research period we have made three significant advances in understanding synaptopathy and protection from it. First, we have shown that female mice are significantly less susceptible to synaptopathy than are males, suggesting that sex hormone provide protection. Second, we have shown effective protection against noise-induced synaptopathy with systemic IEM-1460 injected intraperitoneally in males and females, possibly making intracochlear injection via surgery unnecessary. Third, we have shown that the GluA2 remains associated with postsynaptic densitiesPSDs during excitotoxic trauma in vitro suggesting that the trauma does not itself increase CP-AMPARs. Interestingly, the effect of noise exposure on GluA2 localization in vivo differs between males and females.
- Medicine and Medical Research