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The Journal of Neuroscience, November 1, 1999, 19(21):9218-9227
Knockdown of AMPA Receptor GluR2 Expression Causes Delayed Neurodegeneration and Increases Damage by Sublethal Ischemia in Hippocampal CA1 and CA3 Neurons
Keiji Oguro, Noriko Oguro, Takashi Kojima, Sonja Y. Grooms, Agata Calderone, Xin Zheng, Michael V. L. Bennett, and R. Suzanne Zukin Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461
Considerable evidence suggests that Ca2+-permeable AMPA receptors are critical mediators of the delayed, selective neuronal death associated with transient global ischemia and sustained seizures. Global ischemia suppresses mRNA and protein expression of the glutamate receptor subunit GluR2 and increases AMPA receptor-mediated Ca2+ influx into vulnerable neurons of the hippocampal CA1 before the onset of neurodegeneration. Status epilepticus suppresses GluR2 mRNA and protein in CA3 before neurodegeneration in this region. To examine whether acute downregulation of the GluR2 subunit, even in the absence of a neurological insult, can cause neuronal cell death, we performed GluR2 "knockdown" experiments. Intracerebral injection of antisense oligodeoxynucleotides targeted to GluR2 mRNA induced delayed death of pyramidal neurons in CA1 and CA3. Antisense-induced neurodegeneration was preceded by a reduction in GluR2 mRNA, as indicated by in situ hybridization, and in GluR2 protein, as indicated by Western blot analysis. GluR2 antisense suppressed GluR2 mRNA in the dentate gyrus but did not cause cell death. The AMPA receptor antagonist 6-cyano-7-nitroquinoxiline-2,3-dione (CNQX) and the Ca2+-permeable AMPA receptor channel blocker 1-naphthyl acetyl spermine protected against antisense-induced cell death. This result indicates that antisense-induced cell death is mediated by Ca2+-permeable AMPA receptors. GluR2 antisense and brief sublethal global ischemia acted synergistically to cause degeneration of pyramidal neurons, consistent with action by a common mechanism. These findings demonstrate that downregulation of GluR2 is sufficient to induce delayed death of specific neuronal populations.
Key words: antisense oligonucleotides; neurodegeneration; AMPA receptors; gene expression; hippocampus; excitotoxicity; cerebral ischemia; status epilepticus
Copyright © 1999 Society for Neuroscience 0270-6474/99/19219218-10$05.00/0
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