There is compelling evidence that initiation and maintenance of epileptic
seizures in
temporal lobe epilepsy (TLE) is facilitated by excessive accumulation in the extracellular (perisynaptic) space of the excitatory
neurotransmitter glutamate (Glu). This review discusses the mechanisms underlying this phenomenon. Glu released from neurons is taken up by astrocytes and activated there by
glutamine synthetase (GS) to form
glutamine (Gln) which upon entry to neurons is degraded back to Glu by
phosphate-activated glutaminase (PAG): this chain of reactions has been defined as the
glutamine/
glutamate/cycle (GGC). In the initial phase of epileptogenesis, increased Glu supply is a consequence of activation of its turnover in GGC by Glu released by a primary chemical or physical stimulus. In chronic TLE, profound
astrogliosis and demise of neurons which culminate in
hippocampal sclerosis, are associated with changes in GGC which act in concert towards increasing the extracellular Glu concentration. Deficiency of GS and of the astrocytic Glu transporter, GLT-1, impede Glu inactivation, whereas Glu release from neurons appears facilitated by activation of PAG and increased activity of the neuronal Glu transporter EAAC1. Conclusions derived from measurements of activities/expression patterns of the GGC
enzymes and transporter moieties find support in metabolic studies employing 13C labeled Glu precursors. Glu reuptake by astrocytes is additionally impeded by unfavorable ion gradients resulting from ion and water dyshomeostasis, and extracellular Glu concentration is further increased by reduction of extracellular space due to
edema and altered cytoarchitecture of the hippocampus. Missing links in the scenario are discussed in concluding comments.