Disruption of the GluR2-NSF interaction protects primary hippocampal neurons from ischemic stress

A specific interaction between the AMPA receptor subunits GluR2 and GluR3 a nd the fusion protein NSF has recently been identified. Disruption of this interaction by adenoviral-mediated expression of a peptide (pep2m) correspo nding to the NSF-binding region of GluR2 results in a dramatic reduction in surface expression of AMPA receptors in primary hippocampal neurons. Here we report that expression of pep2m from a recently developed neuronal-speci fic adenoviral system gave significant neuroprotection to primary CA1-CA3 h ippocampal neurons following stimulation with kainate (KA) and this was acc ompanied by a reduction in Ca2+ influx. Protection was also observed follow ing glucose deprivation and exposure to ischemic buffer in the absence of a ny NMDA receptor antagonists. These results provide strong evidence that AM PA receptors play a direct role in mediating postischemic neurotoxicity.