Regulated expression of surface AMPA receptors reduces excitotoxicity in auditory neurons

Dynamic regulation of the expression of surface AMPA receptors (AMPARs) is a key mechanism to modulate synaptic strength and efficacy in the CNS and also to regulate auditory sensitivity. Here we address the role of surface AMPAR expression in excitotoxicity by blocking clathrin-mediated AMPAR endocytosis in auditory neurons. We used a membrane-permeable, dynamin-derived, myristoylated peptide (myr-Dyn) to inhibit surface AMPAR endocytosis induced by glutamate receptor agonists in culture and by noise exposure in vivo. Myr-Dyn infused into the mouse cochlea induced excitotoxic responses to acoustic stimuli that were normally not excitotoxic. These included vacuolization in the nerve terminals and spiral ganglion as well as irreversible auditory brain stem response threshold shifts. In cultured spiral ganglion neuronal cells, blockade of the reduction of surface AMPARs exacerbated neuronal death by incubation with N-methyl-d-aspartate and AMPA. This excitotoxic neuronal death could be prevented by calpeptin, a calpain-specific inhibitor. These results suggest that the reduction of surface AMPAR by endocytosis during excitatory stimulation plays an important role in limiting the excitotoxic damage to the neuron.