Research ReportChronic electrographic seizure reduces glutamine and elevates glutamate in the extracellular fluid of rat brain

Effects of spontaneous seizures on extracellular glutamate and glutamine were studied in the kainate-induced rat model of epilepsy in the chronic phase. Extracellular fluid from the CA1-CA3 regions of the hippocampus was collected with a 2-mm microdialysis probe every 2 min for 5 h. EEG seizures with no or mild behavioral components caused 2- to 6-fold elevation of extracellular glutamate. Concomitantly, extracellular glutamine decreased at t = 5 h to 48% of the initial value (n = 6). The changes in extracellular glutamate and glutamine correlated with the frequency and magnitude of seizure activity. In contrast, no change in either metabolite was observed in kainate-injected rats that did not undergo seizure during microdialysis (n = 6). In hippocampal tissue (9.4 ± 1.1 mg) that contained the region sampled by microdialysis and the site of kainate injection, intracellular glutamine concentration was significantly reduced in the seizure group, compared to that in no-seizure group. The observed elevation of extracellular glutamate strongly suggests that neurotransmitter glutamate was released at a rate faster than the rate of its uptake into glia, possibly due to down-regulation of the transporter. This reduces the availability of substrate glutamate for glutamine synthesis, as corroborated by the observed reduction of intracellular glutamine. This is likely to reduce the rate of glutamine efflux from glia and result in the observed decrease of extracellular glutamine. There remains an intriguing possibility that seizure-induced decrease of extracellular glutamine also reflects its increased uptake into neurons to replenish neurotransmitter glutamate during enhanced epileptiform activity.

Research Highlights► Mild chronic seizures elevate extracellular glutamate in kainate model of epilepsy. ► Seizure-induced decrease of extracellular glutamine is observed for the first time. ► These changes correlate with the frequency and amplitude of EEG seizures. ► Disruption of glutamate-glutamine cycle is implicated in epileptic activity. ► This model closely resembles abnormalities of human temporal-lobe epilepsy.