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

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 alpha-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 Ca(2+)/Zn(2+)-permeable, Glu receptor 2 (GluR2)-lacking AMPARs before the rise in Zn(2+) 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 Zn(2+) 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 Zn(2+) and death of CA1 neurons, although a direct action at the time of the rise in Zn(2+) is unproven. This receptor subtype appears to be an important therapeutic target for intervention in ischemia-induced neuronal death in humans.

• Authors: Kyung-Min Noh, Hidenori Yokota, Toshihiro Mashiko, Pablo E Castillo, R Suzanne Zukin, Michael V L Bennett
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 34 Pg. 12230-5 (Aug 23 2005) ISSN: 0027-8424 [Print] United States
• PMID: 16093311 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• RE1-silencing transcription factor
• Receptors, AMPA
• Repressor Proteins
• Transcription Factors
• 1-naphthylacetylspermine
• Spermine
• Zinc
• Calcium

Topics

• Animals
• Brain Ischemia (metabolism, physiopathology)
• Calcium (metabolism)
• Cell Death (drug effects, physiology)
• Electrophysiology
• Hippocampus (cytology, metabolism)
• Histological Techniques
• Male
• Neurons (drug effects, metabolism, pathology)
• Rats
• Rats, Sprague-Dawley
• Receptors, AMPA (antagonists & inhibitors)
• Repressor Proteins (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Spermine (analogs & derivatives, pharmacology)
• Transcription Factors (metabolism)
• Zinc (metabolism)