Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global schemia-induced death

Kyung Min Noh, Hidenori Yokota, Toshihiro Mashiko, Pablo E. Castillo, R. Suzanne Zukin, Michael V.L. Bennett

Research output: Contribution to journalArticle

165 Scopus citations

Abstract

Transient global or forebrain ischemia induced experimentally in animals can cause selective, delayed neuronal death of hippocampal CA1 pyramidal neurons. A striking feature is a delayed rise in intracellular free Zn 2+ in CA1 neurons just before the onset of histologically detectable cell death. Here we show that α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) at Schaffer collateral to CA1 synapses in postischemic hippocampus exhibit properties of Ca2+/Zn2+-permeable, Glu receptor 2 (GluR2)-lacking AMPARs before the rise in Zn2+ and cell death. At 42 h after ischemia, AMPA excitatory postsynaptic currents exhibited pronounced inward rectification and marked sensitivity to 1-naphthyl acetyl spermine (Naspm), a selective channel blocker of GluR2-lacking AMPARs. In control hippocampus, AMPA excitatory postsynaptic currents were electrically linear and relatively insensitive to Naspm. Naspm injected intrahippocampally at 9-40 h after insult greatly reduced the late rise in intracellular free Zn2+ in postischemic CA1 neurons and afforded partial protection against ischemia-induced cell death. These results implicate GluR2-lacking AMPA receptors in the ischemia-induced rise in free Zn2+ and death of CA1 neurons, although a direct action at the time of the rise in Zn2+ is unproven. This receptor subtype appears to be an important therapeutic target for intervention in ischemia-induced neuronal death in humans.

Original languageEnglish (US)
Pages (from-to)12230-12235
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number34
DOIs
StatePublished - Aug 23 2005

Keywords

  • 1-naphthyl acetyl spermine
  • Glutamate
  • Neurodegeneration

ASJC Scopus subject areas

  • General

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