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Volume 17, Number 16,
Issue of August 15, 1997
pp. 6179-6188
Copyright ©1997 Society for Neuroscience
Global Ischemia Induces Downregulation of Glur2 mRNA and
Increases AMPA Receptor-Mediated Ca2+ Influx in Hippocampal
CA1 Neurons of Gerbil
Received March 19, 1997; revised April 30, 1997; accepted May 28, 1997.
Jan A. Gorter1,
Jeffrey
J. Petrozzino2,
Eleonora M. Aronica1,
Daniel M. Rosenbaum1,
Thoralf Opitz1,
Michael V. L. Bennett1,
John A. Connor2, and
R. Suzanne Zukin1
1 Department of Neuroscience, Albert Einstein College
of Medicine, Bronx, New York 10461, and 2 Roche Institute
of Molecular Biology, Roche Research Center, Nutley, New Jersey 07110
Transient, severe forebrain or global ischemia leads to delayed
cell death of pyramidal neurons in the hippocampal CA1. The precise
molecular mechanisms underlying neuronal cell death after global
ischemia are as yet unknown. Glutamate receptor-mediated Ca2+ influx is thought to play a critical role in
this cell death. In situ hybridization revealed that the
expression of mRNA encoding GluR2 (the subunit that limits
Ca2+ permeability of AMPA-type glutamate receptors)
was markedly and specifically reduced in gerbil CA1 pyramidal neurons
after global ischemia but before the onset of neurodegeneration. To
determine whether the change in GluR2 expression is functionally
significant, we examined the AMPA receptor-mediated rise in cytoplasmic
free Ca2+ level
([Ca2+]i) in individual CA1
pyramidal neurons by optical imaging with the Ca2+
indicator dye fura-2 and by intracellular recording. Seventy-two hours
after ischemia, CA1 neurons that retained the ability to fire action
potentials exhibited a greatly enhanced AMPA-elicited rise in
[Ca2+]i. Basal
[Ca2+]i in these neurons was
unchanged. These findings provide evidence for Ca2+
entry directly through AMPA receptors in pyramidal neurons destined to
die. Downregulation of GluR2 gene expression and an increase in
Ca2+ influx through AMPA receptors in response to
endogenous glutamate are likely to contribute to the delayed neuronal
death after global ischemia.
Key words:
global ischemia;
glutamate receptor regulation;
AMPA
receptor;
GluR2;
GluRB;
hippocampus;
CA1;
intracellular calcium;
intracellular recording;
neurodegeneration;
delayed neurodegeneration;
optical imaging;
gerbil
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