Glutamate release in severe brain ischaemia is mainly by reversed uptake

Abstract

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.

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

“…Indeed, stress has been shown to increase extracellular glutamate concentrations in many brain areas (Lowy et al, 1993;Moghaddam et al, 1994;SteinBehrens et al, 1994), an effect that is proposed to result from compromised activity of the energy-dependent excitatory amino acid transporters. On the other hand, it has recently been shown that glutamate release is mainly due to reversed operation of neuronal glutamate transporters in processes such as brain ischemia and others (Warner et al, 1996;Jabaudon et al, 2000;Rossi et al, 2000). Thus, in stress, this is one among the various mechanisms, which, alone or combined, may be responsible for glutamate release (Lawrence and Sapolsky, 1994) although we have not seen modifications in glutamate uptake in neurons (EAAT-3).…”

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…Thus, A 2A R activation can inhibit glutamate transport into astrocytes [261], in particular GLT-1 [40] and enhance the release of glutamate from astrocytes [39,40]. However, strong arguments have been provided to support the view that the role of glutamate transporters during stressful stimuli is to contribute for the extracellular build-up of glutamate rather than for its removal (see, e.g., [262]). In conclusion, it remains to be determined what might be the contribution of the A 2A R modulation of astrocytic glutamate transporters in the realm of the neuroprotection afforded by A 2A R antagonists in noxious brain conditions.…”

General versus Specific Actions of Mild-Moderate Hypothermia in Attenuating Cerebral Ischemic Damage

“…As we discussed, various studies have shown strikingly consistent results about the effect of hypothermia on AD in global ischemia, probably because the way of detecting AD using direct current potential electrodes is simple and straightforward. However, for glutamate release detection, samples are usually collected using microdialysis probes and are then measured by high-performance liquid chromatography (Li et al, 1999;Phillis et al, 2000;Rossi et al, 2000;Zhao et al, 1999). Extracellular glutamate enters the probe through a semipermeable membrane and is washed out by a continuous flow of solution.…”