title: Glutamate receptor changes associated with transient anoxia/hypoglycaemia in hippocampal slice cultures.
abstract: Transient anoxia/hypoglycaemia in organotypic hippocampal slice cultures, a model of transient brain ischaemia, ultimately results in delayed cell death. Although the mechanisms underlying this delayed death remain unknown, an increase in excitatory drive has been postulated. We report here that transient anoxia/hypoglycaemia in rat hippocampal slice cultures resulted in a 70-80% enhancement of evoked, alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) receptor-mediated, excitatory responses lasting over 60 min. This effect was prevented by blockade of N-methyl-d-aspartate (NMDA) receptors, did not involve changes of paired-pulse facilitation ratio, but was associated with a 50% increase in amplitude, but not frequency, of spontaneous miniature excitatory postsynaptic currents (mEPSCs). Consistent with this, paired recordings revealed the appearance of AMPA receptor-mediated EPSCs at previously silent synapses and occlusion by prior induction of long-term potentiation (LTP). Transient anoxia/hypoglycaemia further resulted in a 63% potentiation of evoked NMDA receptor-dependent synaptic responses, accounting for the 20% increase in ratio of AMPA to NMDA responses. No change in rectification properties of AMPA receptor-mediated currents could be detected within the first hour following anoxia/hypoglycaemia-induced potentiation. Western blot analyses of slice cultures exposed to either control conditions or a short anoxia/hypoglycaemia revealed a marked, 50-70% increase of GluR1, GluR2/3 and NR1 subunits 1 h, but not 15 min, after the anoxic/hypoglycaemic episode. This increase was blocked by an inhibitor of protein synthesis. Together these results indicate that a transient anoxia/hypoglycaemia is associated with a marked enhancement of excitatory transmission sharing similarities with the mechanisms underlying LTP, and is correlated with an increased synthesis of excitatory receptor subunits.
authors.affiliation: Department of Basic Neurosciences, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: Quintana
authors.forename: Stefano
authors.initials: S
authors.lastname: Alberi
authors.forename: David
authors.initials: D
authors.lastname: Hakkoum
authors.forename: Dominique
authors.initials: D
authors.lastname: Muller
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism* / Q000473:pathology*; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology*; D066298:In Vitro Techniques; D016202:N-Methylaspartate / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism*; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D018690:Excitatory Amino Acid Agonists; D017470:Receptors, Glutamate; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid