Prevention of Noise Damage to Cochlear Synapses

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. We showed that a selective blocker of CP-AMPARs -- the anandamide compound IEM-1460 -- reduces synaptopathy caused by application of the glutamate agonist kainic acid to cochlear explants in vitro. We further showed that IEM-1460 inhibits KA-dependent Ca2 entry into spiral ganglion neurons in vitro. Most significantly, we have used physiological measures -- auditory brainstem response threshold and amplitude -- and direct counting of synapses in confocal microscope images to demonstrate essentially complete prevention of synaptopathy and hearing impairment in noise-exposed mice without significant elevation of normal hearing threshold. This suggests that selective CP-AMPAR blockers such as IEM-1460 could be effective in protecting cochlear synapses from noise-induced synaptopathy and preventing the consequent hearing impairment.