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This Article Full Text Full Text (PDF) All Versions of this Article: 102/2/1152    most recent 00288.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Chen, Z. Articles by Sewell, W. F. PubMed PubMed Citation Articles by Chen, Z. Articles by Sewell, W. F.

Regulated Expression of Surface AMPA Receptors Reduces Excitotoxicity in Auditory Neurons

¹Department of Otology and Laryngology, Harvard Medical School; ²Eaton-Peabody Laboratory, Department of Otolaryngology; ³Department of Audiology, Massachusetts Eye and Ear Infirmary; and ⁴Program in Neuroscience, Harvard Medical School, Boston, Massachusetts

Submitted 31 March 2009; accepted in final form 5 June 2009

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.