The Journal of Neurophysiology Vol. 87 No. 6 June 2002, pp. 2896-2903
Copyright ©2002 by the American Physiological Society

NMDA Receptor Activation Mediates Hydrogen Peroxide-Induced Pathophysiology in Rat Hippocampal Slices

Departments of Physiology and Neuroscience and Neurosurgery, New York University School of Medicine, New York, New York 10016

Avshalumov, Marat V. and Margaret E. Rice. NMDA Receptor Activation Mediates Hydrogen Peroxide-Induced Pathophysiology in Rat Hippocampal Slices. J. Neurophysiol. 87: 2896-2903, 2002. Endogenous reactive oxygen species (ROS) can act as modulators of neuronal activity, including synaptic transmission. Inherent in this process, however, is the potential for oxidative damage if the balance between ROS production and regulation becomes disrupted. Here we report that inhibition of synaptic transmission in rat hippocampal slices by H₂O₂ can be followed by electrical hyperexcitability when transmission returns during H₂O₂ washout. As in previous studies, H₂O₂ exposure (15 min) reversibly depressed the extracellular population spike (PS) evoked by Schaffer collateral stimulation. Recovery of PS amplitude, however, was typically accompanied by mild epileptiform activity. Inclusion of ascorbate (400 µM) during H₂O₂ washout prevented this pathophysiology. No protection was seen with isoascorbate, which is a poor substrate for the stereoselective ascorbate transporter and thus remains primarily extracellular. Epileptiform activity was also prevented by the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (AP5) during H₂O₂ washout. Once hyperexcitability was induced, however, AP5 did not reverse it. When present during H₂O₂ exposure, AP5 did not alter PS depression by H₂O₂ but did inhibit the recovery of PS amplitude seen during pulse-train stimulation (10 Hz, 5 s) in H₂O₂. Inhibition of glutamate uptake by l-trans-2,4-pyrrolidine dicarboxylate (PDC; 50 µM) during H₂O₂ washout markedly enhanced epileptiform activity; coapplication of ascorbate with PDC prevented this. These data indicate that H₂O₂ exposure can cause activation of normally silent NMDA receptors, possibly via inhibition of redox-sensitive glutamate uptake. When synaptic transmission returns during H₂O₂ washout, enhanced NMDA receptor activity leads to ROS generation and consequent oxidative damage. These data reveal a pathological cycle that could contribute to progressive degeneration in neurological disorders that involve oxidative stress, including cerebral ischemia.