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 receptors are responsible for neuronal damage that occurs after an ischemic or hypoxic episode. In the present work, we investigated the relative contribution of presynaptic and postsynaptic blockade of synaptic transmission, as well as of blockade of NMDA receptors, for the facilitation of recovery of synaptic transmission in the CA1 area of rat hippocampal slices exposed to prolonged (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 antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), recovery of synaptic transmission from hypoxia was significantly attenuated, and this impairment could be overcome by preventing synaptic transmission during hypoxia either with 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 synaptic transmission was allowed to occur during hypoxia, because of the presence of DPCPX, there was an NMDA receptor-mediated component of the EPSCs recorded in CA1 pyramidal neurons, and blockade of NMDA receptors with AP-5 restored recovery of synaptic transmission from hypoxia. It is concluded that 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 facilitates recovery.
Sebastião
A M
AM
Laboratory of Neurosciences, Faculty of Medicine of Lisbon, 1649-028 Lisbon, Portugal. anaseb@neurociencias.pt
de Mendonca
A
A
Moreira
T
T
Ribeiro
J A
JA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D002534:Hypoxia, Brain / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate; D014970:Xanthines; D013779:Tetrodotoxin; D016202:N-Methylaspartate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D010100:Oxygen