Colbourne Frederick, Grooms Sonja Y, Zukin R Suzanne, Buchan Alastair M, Bennett Michael V L
Department of Psychology, Faculty of Science, University of Alberta, Edmonton, AB, Canada T6G 2E9.
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2906-10. doi: 10.1073/pnas.2628027100. Epub 2003 Feb 26.
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."
啮齿动物短暂性前脑缺血会导致选择性和延迟性神经元死亡，尤其是海马CA1锥体神经元。神经元死亡之前，CA1区特异性下调GluR2，即α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体亚基，该亚基可限制Ca(2+)内流。据推测，这种改变通过允许Ca(2+)和/或Zn(2+)通过新形成的缺乏GluR2的AMPA受体致命性内流而导致神经变性。缺血后1小时诱导的两天轻度低温可有效且持久地保护免受缺血性损伤。我们研究了低温诱导神经保护作用的分子机制。我们报告，低温可使大多数海马CA1神经元免受缺血诱导的细胞死亡，并减弱缺血诱导的编码AMPA受体亚基GluR2的mRNA下调。通过定量原位杂交评估，缺血在2天时诱导CA1区GluR2 mRNA明显下调，GluR1 mRNA小幅下调。缺血诱导的基因表达变化具有细胞特异性，因为CA3区或齿状回中的GluR2没有明显改变。低温治疗缺血后，GluR2 mRNA表达在2天时略有降低，并在7天时完全恢复到对照水平。低温可防止缺血诱导的GluR1 mRNA表达变化。这些发现表明，在GluR2基因转录调控水平进行干预可能是缺血后长时间低温挽救否则“注定死亡”的CA1神经元的一种机制。
