An Electrophysiological Measure of NMDA Activation in Perforant Path Kindling

Abstract

High frequency stimulation of the perforant pathway triggers a prolonged field potential in the dentate gyrus that far outlasts that obtained with single pulses. The late rising component of this field potential has recently been shown to be mediated by N-methyl-D-aspartate (NMDA). In the present thesis, rats were implanted with stimulating electrodes in the perforant pathway and recording electrodes in the dentate gyrus of the hippocampus. Baseline input/output functions of field potentials (or population EPSPs) were established for each rat. Ketamine, an NMDA receptor antagonist, was then administered to confirm its effects on the late component of the EPSP. The late component was measured by subtracting the pulse-evoked from the train-evoked response. Ketamine was shown to significantly attenuate the late component. Diazepam, a GABA agonist, had no significant effect on the late component. Having established an NMDA component in the field potential allows for the monitoring of the levels of NMDA activation over prolonged periods. Hence, the effect of kindling, an animal model of temporal lobe epilepsy, was also determined. Fully kindled rats--defined as those who had experienced four stage 5 seizures--also had significantly attenuated late components. In contrast to decreased late components, kindled rats displayed increased population spike amplitudes and EPSP slopes. Such a decrease in the late component suggests that the NMDA receptor plays a role in kindling. Subjects were also given ketamine and diazepam following kindling, whereby the effects were proportionately the same as those observed prior to kindling.