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(Stroke. 2002;33:1698.)
© 2002 American Heart Association, Inc.

Original Contributions

[³H]Muscimol Binding to -Aminobutyric Acid_A Receptors Is Upregulated in CA1 Neurons of the Gerbil Hippocampus in the Ischemia-Tolerant State

Clemens Sommer, MD; Alexander Fahrner Marika Kiessling, MD

From the Department of Neuropathology, Ruprecht-Karls University of Heidelberg, Heidelberg, Germany.

Correspondence to Clemens Sommer, MD, Laboratory of Neuropathology, Department of Pathology, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany. E-mail clemens.sommer{at}medizin.uni-ulm.de

Background and Purpose— 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 -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]-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.

Key Words: autoradiography • excitotoxicity • ischemia • neuroprotection • receptors, AMPA • receptors, GABA-A • gerbils

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