Activation of synaptic NMDA receptors by action potential-dependent release of transmitter during hypoxia impairs recovery of synaptic transmission on reoxygenation

Increased levels of glutamate and the subsequent activation of NMDA recepto rs are responsible for neuronal damage that occurs after an ischemic or hyp oxic episode. In the present work, we investigated the relative contributio n of presynaptic and postsynaptic blockade of synaptic transmission, as wel l as of blockade of NMDA receptors, for the facilitation of recovery of syn aptic transmission in the CA1 area of rat hippocampal slices exposed to pro longed (90 min) hypoxia. During hypoxia, there was a complete inhibition of field EPSPs, which was fully reversible if released adenosine was allowed to act. When adenosine A(1) receptors were blocked with the selective antag onist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), recovery of synaptic tran smission from hypoxia was significantly attenuated, and this impairment cou ld be overcome by preventing synaptic transmission during hypoxia either wi th tetrodotoxin (TTX) or by switching off the afferent stimulation but not by postsynaptic blockade of transmission with 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) or selective blockade of adenosine A(2A) receptors. When syn aptic transmission was allowed to occur during hypoxia, because of the pres ence of DPCPX, there was an NMDA receptor-mediated component of the EPSCs r ecorded in CA1 pyramidal neurons, and blockade of NMDA receptors with AP-5 restored recovery of synaptic transmission from hypoxia. It is concluded th at impairment of recovery of synaptic transmission after an hypoxic insult results from activation of synaptic NMDA receptors by synaptically released glutamate and that adenosine by preventing this activation efficiently fac ilitates recovery.