Ischemic disruption of glutamate homeostasis in brain: quantitative immunocytochemical analyses.
More than 10 years ago, it was shown by microdialysis that the excitatory transmitter glutamate accumulates in the interstitial space of brain subjected to ischemic insult. This was one of the key observations leading to the formulation of the "glutamate hypothesis' of ischemic cell death. It is now assumed that even a transient glutamate overflow may set in motion a number of events that ultimately cause cell loss in vulnerable neuronal populations. The aim of the present review is to discuss the intracellular changes that underlie the dysregulation of extracellular glutamate during and after ischemia, with emphasis on data obtained by postembedding, electron microscopic immunogold cytochemistry. While the time resolution of this approach is necessarily limited, it can reveal, quantitatively and at a high level of spatial resolution, how the intracellular pools of glutamate and metabolically related amino acids are perturbed during and after an ischemic insult. Moreover, this can be done in animals whose extracellular amino acid levels are monitored by microdialysis, allowing a direct correlation of extra- and intracellular changes. Immunogold analyses of brains subjected to ischemia have identified dendrites and neuronal somata as likely sources of glutamate efflux, probably mediated by reversal of glutamate uptake. The vesicular glutamate pool has been found to be largely unchanged after 20 min of ischemia. Ischemia causes an increased glutamate content and an increased glutamate/glutamine ratio in glial cells, as revealed by double immunogold labelling. This argues against the idea that glial cells contribute to the extracellular overflow of glutamate in the ischemic brain.
Ottersen
O P
OP
Department of Anatomy, University of Oslo, Blindern, Norway. o.p.ottersen@basalmed.uio.no
Laake
J H
JH
Reichelt
W
W
Haug
F M
FM
Torp
R
R
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism*; D002451:Cell Compartmentation; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D016014:Linear Models; D016253:Microscopy, Immunoelectron; D012016:Reference Values
D018698:Glutamic Acid