Abstracts

RATIONALE:_Numerous in vivo and in vitro models of epileptiform activity have been developed to explore the underlying mechanisms of epilepsy. Epileptic seizures are observed in mice that do not express the glial glutamate transporter, GLT-1 in vivo. In vitro, the simultaneous discharge of hippocampal CA3 pyramidal cells is a widely studied model of physiological and pathological network synchronization. We examined whether clearance of glutamate from the synaptic cleft alters the bursting of CA3 neurons in the hippocampal slice. METHODS:_Whole-cell recordings were obtained from CA3 neurons of the adult rat hippocampus in 400?m thick slices at 35 C. Experiments were conducted in which we pharmacologically blocked the active re-uptake of glutamate from the synaptic cleft. RESULTS:_Application of the re-uptake inhibitor, dihydrokainate (DHK)(50?M-300?M) increased both the amplitude and frequency of spontaneous EPSCs. This increase in excitability was sufficient to elicit synchronous network discharges in slices that were quiescent prior to DHK application. This was followed by a depression of network and synaptic activity. This depression was not due to activation of presynaptic mGluRs since 500 ?M MCPG failed to prevent synaptic or network depression. Bath application of 100?M glutamate also failed to depress the synapses suggesting that a slow desensitization of postsynaptic glutamate receptors was not involved in this process. CONCLUSIONS:These findings suggest that rapid re-uptake of glutamate is necessary not only to prevent the onset of CA3 network discharges, but also to sustain synaptic transmission. Consistent with this idea, spontaneous events late in an ictal discharge of kainate treated rats closely resemble those observed during in vitro CA3 recordings when glutamate re-uptake is inhibited. This suggests that late in the seizure, glutamate re-uptake may be compromised and that glutamate transporters may represent novel therapeutic targets in the treatment of epilepsy. SUPPORT: NS344360, NS34700, JSB is a fellow of the Epilepsy Foundation of America