Glutamate release in severe brain ischaemia is mainly by reversed uptake.
The release of glutamate during brain anoxia or ischaemia triggers the death of neurons, causing mental or physical handicap. The mechanism of glutamate release is controversial, however. Four release mechanisms have been postulated: vesicular release dependent on external calcium or Ca2+ released from intracellular stores; release through swelling-activated anion channels; an indomethacin-sensitive process in astrocytes; and reversed operation of glutamate transporters. Here we have mimicked severe ischaemia in hippocampal slices and monitored glutamate release as a receptor-gated current in the CA1 pyramidal cells that are killed preferentially in ischaemic hippocampus. Using blockers of the different release mechanisms, we demonstrate that glutamate release is largely by reversed operation of neuronal glutamate transporters, and that it plays a key role in generating the anoxic depolarization that abolishes information processing in the central nervous system a few minutes after the start of ischaemia. A mathematical model incorporating K+ channels, reversible uptake carriers and NMDA (N-methyl-D-aspartate) receptor channels reproduces the main features of the response to ischaemia. Thus, transporter-mediated glutamate homeostasis fails dramatically in ischaemia: instead of removing extracellular glutamate to protect neurons, transporters release glutamate, triggering neuronal death.
Rossi
D J
DJ
Department of Physiology, University College London, UK.
Oshima
T
T
Attwell
D
D
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects; D008959:Models, Neurological; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D009435:Synaptic Transmission
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D018691:Excitatory Amino Acid Antagonists; D015221:Potassium Channels; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D011188:Potassium; D002118:Calcium; D007213:Indomethacin