title: Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia.
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 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."
authors.affiliation: Department of Psychology, Faculty of Science, University of Alberta, Edmonton, AB, Canada T6G 2E9. fcolbour@ualberta.ca
authors.forename: Frederick
authors.initials: F
authors.lastname: Colbourne
authors.forename: Sonja Y
authors.initials: SY
authors.lastname: Grooms
authors.forename: R Suzanne
authors.initials: RS
authors.lastname: Zukin
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Buchan
authors.forename: Michael V L
authors.initials: MV
authors.lastname: Bennett
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005849:Gerbillinae; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism*; D007035:Hypothermia; D017403:In Situ Hybridization; D007511:Ischemia; D008297:Male; D016548:Prosencephalon / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*; D013696:Temperature; D013997:Time Factors; D014158:Transcription, Genetic; D015032:Zinc / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D018091:Receptors, AMPA; D015032:Zinc; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium