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Brief forebrain ischemia in rodents induces selective and delayed neuronal death, particularly of hippocampal CA1 pyramidal neurons. Neuronal death is preceded by down-regulation specific to CA1 of GluR2, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit that limits Ca(2+) influx. This alteration is hypothesized to cause neurodegeneration by permitting a lethal influx of Ca(2+) and/or Zn(2+) through newly formed GluR2-lacking AMPA receptors. Two days of mild hypothermia induced 1 h after ischemia potently and lastingly protects against ischemic injury. We examined molecular mechanisms underlying hypothermia-induced neuroprotection. We report that hypothermia rescues most hippocampal CA1 neurons from ischemia-induced cell death and attenuates ischemia-induced down-regulation of mRNA encoding the AMPA receptor subunit GluR2. Ischemia induced a marked down-regulation of GluR2 mRNA and a small down-regulation of GluR1 mRNA in CA1 at 2 days, as assessed by quantitative in situ hybridization. The ischemia-induced changes in gene expression were cell-specific in that GluR2 was not significantly altered in CA3 or dentate gyrus. After ischemia treated by hypothermia GluR2 mRNA expression was modestly reduced at 2 days and exhibited complete recovery to control levels at 7 days. Hypothermia prevented ischemia induced changes in GluR1 mRNA expression. These findings suggest that intervention at the level of transcriptional regulation of the GluR2 gene may be a mechanism by which prolonged postischemic cooling rescues CA1 neurons otherwise "destined to die."

Original publication

DOI

10.1073/pnas.2628027100

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

04/03/2003

Volume

100

Pages

2906 - 2910

Keywords

Animals, Brain, Calcium, Down-Regulation, Female, Gerbillinae, Hippocampus, Hypothermia, In Situ Hybridization, Ischemia, Male, Prosencephalon, RNA, Messenger, Receptors, AMPA, Temperature, Time Factors, Transcription, Genetic, Zinc