Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death.
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.
Noh
Kyung-Min
KM
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Yokota
Hidenori
H
Mashiko
Toshihiro
T
Castillo
Pablo E
PE
Zukin
R Suzanne
RS
Bennett
Michael V L
MV
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006652:Histological Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D015032:Zinc / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
D002118:Calcium; D018091:Receptors, AMPA; D012097:Repressor Proteins; D013096:Spermine; D014157:Transcription Factors; D015032:Zinc; D000099229:RE1-Silencing Transcription Factor; C067506:1-naphthylacetylspermine