Altered interaction between PSD-95 and the NMDA receptor following transient global ischemia

The postsynaptic density (PSD) is a cytoskeletal specialization involved in the anchoring of neurotransmitter receptors and in regulating the response of postsynaptic neurons to synaptic stimulation. The postsynaptic protein PSD-95 binds to NMDA receptor subunits NR2A and NR2B and to signaling molec ules such as neuronal nitric oxide synthase and p135synGAP. We investigated the effects of transient cerebral ischemia on protein interactions involvi ng PSD-95 and the NMDA receptor in the rat hippocampus. Ischemia followed b y reperfusion resulted in a decrease in the solubility of the NMDA receptor and PSD-95 in 1% sodium deoxycholate, the decrease being greater in the vu lnerable CAI hippocampal subfield than in the less sensitive CA3/dentate gy rus regions. Solubilization of the kainic acid receptor Glu6/7 and the PSD- 95 binding proteins, neuronal nitric oxide synthase and p135synGAP, also de creased following ischemia. The association between PSD-95 and NR2A and NR2 B, as indicated by coimmunoprecipitation, was less in postischemic samples than in sham-operated controls. Ischemia also resulted in a decrease in the sire of protein complexes containing PSD-95, but had only a small effect o n the size distribution of complexes containing the NMDA receptor. The resu lts indicate that molecular interactions involving PSD-95 and the NMDA rece ptor are modified by an ischemic challenge.