Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia

Frederick Colbourne, Sonja Y. Grooms, R. Suzanne Zukin, Alastair M. Buchan, Michael V.L. Bennett

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit that limits Ca2+ influx. This alteration is hypothesized to cause neurodegeneration by permitting a lethal influx of Ca2+ and/or Zn2+ 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 languageEnglish (US)
Pages (from-to)2906-2910
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number5
DOIs
StatePublished - Mar 4 2003

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Keywords

  • Cerebral ischemia
  • Global ischemia
  • GluR1
  • Hippocampus
  • Neuroprotection

ASJC Scopus subject areas

  • General

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