Glutamate release in severe brain ischaemia is mainly by reversed uptake

The release of glutamate during brain anoxia or ischaemia triggers the deat h of neurons', causing mental or physical handicap. The mechanism of glutam ate release is controversial, however. Four release mechanisms have been po stulated: vesicular release dependent on external calcium(2) or Ca2+ releas ed from intracellular stores(3); release through swelling-activated onion c hannels(4); an indomethacin-sensitive process in astrocytes(5-7); and rever sed operation of glutamate transporters(8,9). Here we have mimicked severe ischaemia in hippocampal slices and monitored glutamate release as a recept or-gated current in the CA1 pyramidal cells that are killed preferentially in ischaemic hippocampus. Using blockers of the different release mechanism s, we demonstrate that glutamate release is largely by reversed operation o f neuronal glutamate transporters, and that it plays a key role in generati ng the anoxic depolarization that abolishes information processing in the c entral nervous system a few minutes after the start of ischaemia. A mathema tical model incorporating K+ channels, reversible uptake carriers and NMDA (N-methyl-D-aspartate) receptor channels reproduces the main features of th e response to ischaemia. Thus, transporter-mediated glutamate homeostasis f ails dramatically in ischaemia: instead of removing extracellular glutamate to protect neurons, transporters release glutamate, triggering neuronal de ath.