title: [3H]muscimol binding to gamma-aminobutyric acid(A) receptors is upregulated in CA1 neurons of the gerbil hippocampus in the ischemia-tolerant state.
abstract: OBJECTIVE
  Excitotoxic activation of glutamate receptors is currently thought to play a pivotal role in delayed neuronal death (DND) of highly vulnerable CA1 neurons in the gerbil hippocampus after transient global ischemia. Postischemic degeneration of these neurons can be prevented by "preconditioning" with a short sublethal ischemic stimulus. The present study was designed to test whether ischemic preconditioning is associated with specific alterations of ligand binding to excitatory glutamate and/or inhibitory gamma-aminobutyric acid (GABA)A receptors compared with ischemia severe enough to induce DND.
  
  
  METHODS
  With the use of quantitative receptor autoradiography, postischemic ligand binding of [3H]MK-801 and [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to excitatory N-methyl-D-aspartate (NMDA) and AMPA receptors as well as [3H]muscimol to inhibitory GABA(A) receptors in hippocampal subfields CA1, CA3, and the dentate gyrus were analyzed in 2 experimental paradigms. Gerbils were subjected to (1) a 5-minute ischemic period resulting in DND of CA1 neurons and (2) a 2.5-minute period of ischemia mediating tolerance induction.
  
  
  RESULTS
  [3H]MK-801 and [3H]AMPA binding values to excitatory NMDA and AMPA receptors showed a delayed decrease in relatively ischemia-resistant CA3 and dentate gyrus despite maintained neuronal cell density. [3H]Muscimol binding to GABA(A) receptors in CA1 neurons was transiently but significantly increased after preconditioning but not after global ischemia with consecutive neuronal death.
  
  
  CONCLUSIONS
  Downregulation of ligand binding to glutamate receptors in relatively ischemia-resistant CA3 and dentate gyrus neurons destined to survive suggests marked synaptic reorganization processes despite maintained structural integrity. More importantly, upregulation of binding to inhibitory GABA(A) receptors in the hippocampus indicates a relative shift between inhibitory and excitatory neurotransmission that we suggest may participate in endogenous postischemic neuroprotection.
authors.affiliation: Department of Neuropathology, Ruprecht-Karls University of Heidelberg, Heidelberg, Germany. clemens.sommer@medizin.uni-ulm.de
authors.forename: Clemens
authors.initials: C
authors.lastname: Sommer
authors.forename: Alexander
authors.initials: A
authors.lastname: Fahrner
authors.forename: Marika
authors.initials: M
authors.lastname: Kiessling
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D018690:Excitatory Amino Acid Agonists / Q000493:pharmacokinetics; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning; D008024:Ligands; D008297:Male; D009118:Muscimol / Q000493:pharmacokinetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011963:Receptors, GABA-A / Q000378:metabolism*; D014316:Tritium; D015854:Up-Regulation; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000493:pharmacokinetics
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D011963:Receptors, GABA-A; D014316:Tritium; D009118:Muscimol; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid