Simplified diagram of the brain glutamate metabolism illustrating the involvement of astrocytes, neurons, transporter molecules, and key enzymes. Note that extracellular glutamate is taken up by the astrocyte via glutamate transporters (GLAST, GLT1) and converted to glutamine by glutamine synthetase (GS) in the astrocyte cytoplasm. Loss of GS is hypothesized to increase glutamate in astrocytes and impair the clearance of extracellular glutamate (Box 1). Increased extracellular glutamate is likely to facilitate the triggering of epileptic seizures (Box 2). Abbreviations: GLUTs, glucose transporters; PAG, phosphate activated glutaminase; MCTs, monocarboxylate transporters; MTLE, mesial temporal lobe epilepsy; PC, pyruvate carboxylase; SAT2, system A transporter 2; SN1, system N transporter 1; VGLUT, vesicular glutamate transporter.