Metabotropic glutamate receptor subtypes differentially influence neuronal recovery from in vitro hypoxia/hypoglycemia in rat hippocampal slices.
Hippocampal slices were transiently exposed to an oxygen- and glucose-free environment which causes a pronounced drop of both ATP and creatine phosphate, an anoxic depolarization, and an incomplete recovery of synaptically evoked population spike in the CA1 region after 1 h (48.5 +/- 3.6% of baseline values). This recovery could be markedly enhanced by the application of N-methyl-D-aspartate receptor antagonists. To examine the influence of metabotropic glutamate receptors on neuronal recovery from hypoxia/hypoglycemia, we applied various antagonists and agonists of the metabotropic glutamate receptors to the bath during the interval from 20 min before to 10 after hypoxia/hypoglycemia. The metabotropic glutamate receptor antagonists (+)-alpha-methyl-4-carboxyphenylglycine and L-2-3- amino-phosphonopropionic acid were both able to enhance the population spike recovery significantly. However, the mixed metabotropic glutamate receptor agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid also exhibited a protective effect on population spike recovery, leaving the anoxic depolarization and N-methyl-D-aspartate responses during the hypoxia/hypoglycemia untouched. With the help of more subtype-specific agonists, we found that an activation of phospholipase C coupled (class 1) metabotropic glutamate receptors prior to hypoxia/hypoglycemia may be responsible for the protective effect seen with 1S, 3R-1-aminocyclopentane-1,3-dicarboxylic acid, because the specific class 1 metabotropic glutamate receptor agonist trans-azetidine-2,4-dicarboxylic acid appeared to be highly protective, but only if it was applied 20 min before the hypoxia/hypoglycemia. An activation of class 2 metabotropic glutamate receptors by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine, which inhibits adenylyl cyclase activity, led to a marked deterioration of the population spike recovery and even to a total prevention of the protective effect of the N-methyl-D-aspartate agonist D-2-amino-5-phosphonopentanoic acid. Our data suggest that prior activation of class 1 metabotropic glutamate receptors is beneficial, while their activation during hypoxia/hypoglycemia is detrimental. Furthermore, the activation of class 2 metabotropic glutamate receptors decreases the recovery from hypoxia/hypoglycemia.
Department of Neurophysiology, Federal Institute for Neurobiology, Magdeburg, Germany.
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T
Opitz
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Richter
A J
AJ
Carter
A P
AP
Kozikowski
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Shinozaki
K G
KG
Reymann
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology; D004734:Energy Metabolism / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007003:Hypoglycemia / Q000473:pathology*; D002534:Hypoxia, Brain / Q000473:pathology*; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009474:Neurons / Q000502:physiology*; D010725:Phosphocreatine / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D010725:Phosphocreatine; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate