title: Mechanisms of Excessive Extracellular Glutamate Accumulation in Temporal Lobe Epilepsy.
abstract: 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 employing13C 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.
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland. jalbrecht@imdik.pan.pl.
authors.forename: Jan
authors.identifier: http://orcid.org/0000-0001-6063-6228
authors.initials: J
authors.lastname: Albrecht
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zielińska
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2; D045604:Extracellular Fluid / Q000378:metabolism*; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C493397:SLC1A2 protein, human; D018698:Glutamic Acid
keywords: Astrocytes; Extracellular glutamate; Glutamine glutamate cycle; Neurons; Temporal lobe epilepsy