Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP

Cerebral ischemia results in activation of the mitogen-activated protein ki nase pathway and increased tyrosine phosphorylation of proteins associated with postsynaptic densities (PSDs). The authors investigated the possible r elation between these events by determining the effect of ischemia on tyros ine phosphorylation of the brain-specific, PSD-enriched, Ras-GTPase activat ing protein, SynGAP. Transient (15 minutes) global ischemia was produced in rats by 4-vessel occlusion and PSDs prepared from forebrains immediately a fter ischemia or at 20 minutes, 1 hour, or 24 hours of reperfusion. Tyrosin e phosphorylation of SynGAP was elevated relative to sham-operated controls by 20 minutes of reperfusion and remained elevated for at least 24 hours. Tyrosine phosphorylation of SynGAP also increased in CAI and CA3/DG subfiel ds of the hippocampus. Enhanced tyrosine phosphorylation of Syn-GAP was not accompanied by a change in PSD RasGAP activity. SynGAP bound to the SH2 do mains of Src and Fyn in a tyrosine phosphorylation-dependent fashion, and t his interaction increased after ischemia. SynGAP binds to the PDZ domains o f PSD-95/SAP90 and coimmunoprecipitated with PSD-95. The coimmunoprecipitat ion of SynGAP with PSD-95 decreased after ischemia. The results indicate th at changes in the properties and interactions of SynGAP may be involved in the neuropathology of ischemia.