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The Journal of Neuroscience, November 1, 2001, 21(21):8564-8571

Activation of Synaptic NMDA Receptors by Action Potential-Dependent Release of Transmitter during Hypoxia Impairs Recovery of Synaptic Transmission on Reoxygenation

Ana M. Sebastião, Alexandre de Mendonça, Tiago Moreira, and J. Alexandre Ribeiro

Laboratory of Neurosciences, Faculty of Medicine of Lisbon, 1649-028 Lisbon, Portugal

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 A₁ 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.

Key words: glutamate; NMDA receptors; adenosine; hypoxia; hippocampus; synaptic transmission

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21218564-08$05.00/0

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