Home LiteratureArticle Details
PMID: 9236229 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Global ischemia induces downregulation of Glur2 mRNA and increases AMPA receptor-mediated Ca2+ influx in hippocampal CA1 neurons of gerbil.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 17 ·No. 16 ·1997-08-15 ·Pages 6179-88

Gorter JA, Petrozzino JJ, Aronica EM, Rosenbaum DM, Opitz T, Bennett MV, Connor JA, Zukin RS

Abstract

Transient, severe forebrain or global ischemia leads to delayed cell death of pyramidal neurons in the hippocampal CA1. The precise molecular mechanisms underlying neuronal cell death after global ischemia are as yet unknown. Glutamate receptor-mediated Ca2+ influx is thought to play a critical role in this cell death. In situ hybridization revealed that the expression of mRNA encoding GluR2 (the subunit that limits Ca2+ permeability of AMPA-type glutamate receptors) was markedly and specifically reduced in gerbil CA1 pyramidal neurons after global ischemia but before the onset of neurodegeneration. To determine whether the change in GluR2 expression is functionally significant, we examined the AMPA receptor-mediated rise in cytoplasmic free Ca2+ level ([Ca2+]i) in individual CA1 pyramidal neurons by optical imaging with the Ca2+ indicator dye fura-2 and by intracellular recording. Seventy-two hours after ischemia, CA1 neurons that retained the ability to fire action potentials exhibited a greatly enhanced AMPA-elicited rise in [Ca2+]i. Basal [Ca2+]i in these neurons was unchanged. These findings provide evidence for Ca2+ entry directly through AMPA receptors in pyramidal neurons destined to die. Downregulation of GluR2 gene expression and an increase in Ca2+ influx through AMPA receptors in response to endogenous glutamate are likely to contribute to the delayed neuronal death after global ischemia.

MeSH Terms
Animals Brain Ischemia/genetics,metabolism Calcium/metabolism Electrophysiology Gene Expression/physiology Gerbillinae Hippocampus/blood supply,cytology Image Processing, Computer-Assisted Male Nerve Degeneration/physiology Pyramidal Cells/chemistry,metabolism RNA, Messenger/metabolism Receptors, AMPA/chemistry,genetics
Chemicals
RNA, Messenger Receptors, AMPA Calcium
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Gorter J A
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Petrozzino J J
Aronica E M
Rosenbaum D M
Opitz T
Bennett M V
Connor J A
Zukin R S
References (59)
59 references, click to expand
  1. The segregation and expression of glutamate receptor subunits in cultured hippocampal neurons.
    Neuroscience. 1993 Dec;57(4):943-64 PMID: 8309554
  2. Ischaemia does not alter the editing status at the Q/R site of glutamate receptor-A, -B, -5 and -6 subunit mRNA.
    Neuroreport. 1995 May 30;6(8):1133-6 PMID: 7662894
  3. Vulnerability of mossy fiber targets in the rat hippocampus to forebrain ischemia.
    J Neurosci. 1993 Sep;13(9):3964-79 PMID: 8366355
  4. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels.
    Cell. 1991 Oct 4;67(1):11-9 PMID: 1717158
  5. Argiotoxin detects molecular differences in AMPA receptor channels.
    Neuron. 1993 Jun;10(6):1131-40 PMID: 7686380
  6. High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus.
    Neuroscience. 1995 Dec;69(4):1031-55 PMID: 8848093
  7. Enhanced LTP in mice deficient in the AMPA receptor GluR2.
    Neuron. 1996 Nov;17(5):945-56 PMID: 8938126
  8. Blockade of the AMPA receptor prevents CA1 hippocampal injury following severe but transient forebrain ischemia in adult rats.
    Neurosci Lett. 1991 Nov 11;132(2):255-8 PMID: 1664505
  9. Expression of AMPA-glutamate receptor B subunit in rat hippocampal GABAergic neurons.
    Eur J Neurosci. 1996 Aug;8(8):1580-90 PMID: 8921250
  10. Effects of a spider toxin and its analogue on glutamate-activated currents in the hippocampal CA1 neuron after ischemia.
    J Neurophysiol. 1995 Jul;74(1):218-25 PMID: 7472325
  11. The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders.
    Trends Neurosci. 1997 Oct;20(10):464-70 PMID: 9347614
  12. Cyclothiazide differentially modulates desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor splice variants.
    Mol Pharmacol. 1994 Jul;46(1):129-38 PMID: 8058047
  13. Proportion of parvalbumin-positive basket cells in the GABAergic innervation of pyramidal and granule cells of the rat hippocampal formation.
    J Comp Neurol. 1990 Oct 22;300(4):449-61 PMID: 2273087
  14. Biphasic expression of the fos and jun families of transcription factors following transient forebrain ischaemia in the rat. Effect of hypothermia.
    Eur J Neurosci. 1995 Oct 1;7(10):2007-16 PMID: 8542058
  15. Selective vulnerability of the hippocampus in brain ischemia.
    Neuroscience. 1991;40(3):599-636 PMID: 1676492
  16. A single amino acid determines the subunit-specific spider toxin block of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor channels.
    Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6528-32 PMID: 8393569
  17. Brain insults in rats induce increased expression of the BDNF gene through differential use of multiple promoters.
    Eur J Neurosci. 1994 Apr 1;6(4):587-96 PMID: 8025713
  18. Combinations of AMPA receptor subunit expression in individual cortical neurons correlate with expression of specific calcium-binding proteins.
    J Neurosci. 1997 Mar 1;17(5):1570-81 PMID: 9030617
  19. Distribution of the excitatory amino acid receptor subunits GluR2(4) in monkey hippocampus and colocalization with subunits GluR5-7 and NMDAR1.
    J Neurosci. 1995 Apr;15(4):2707-19 PMID: 7722624
  20. Blockade of ornithine decarboxylase enzyme protects against ischemic brain damage.
    J Cereb Blood Flow Metab. 1994 Nov;14(6):1040-5 PMID: 7929646
  21. Kainate-induced status epilepticus alters glutamate and GABAA receptor gene expression in adult rat hippocampus: an in situ hybridization study.
    J Neurosci. 1994 May;14(5 Pt 1):2697-707 PMID: 8182436
  22. Correlation between kinetics and RNA splicing of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in neocortical neurons.
    Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1797-802 PMID: 8700838
  23. Calcium permeability of glutamate-gated channels in the central nervous system.
    Curr Opin Neurobiol. 1996 Jun;6(3):311-7 PMID: 8794087
  24. Are Ca(2+)-permeable kainate/AMPA receptors more abundant in immature brain?
    Neurosci Lett. 1992 Sep 14;144(1-2):65-9 PMID: 1331916
  25. Alterations of the GluR-B AMPA receptor subunit flip/flop expression in kainate-induced epilepsy and ischemia.
    Neuroscience. 1993 Dec;57(3):545-54 PMID: 8309523
  26. Kainic acid-induced lipid peroxidation: protection with butylated hydroxytoluene and U78517F in primary cultures of cerebellar granule cells.
    Brain Res. 1993 Oct 8;624(1-2):223-32 PMID: 8252395
  27. Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons.
    J Neurosci. 1996 Mar 15;16(6):1982-9 PMID: 8604042
  28. Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice.
    Science. 1995 Dec 8;270(5242):1677-80 PMID: 7502080
  29. Cerebral hypoxia: some new approaches and unanswered questions.
    J Neurosci. 1990 Aug;10(8):2493-501 PMID: 1974918
  30. Temporal profile of neuronal damage in a model of transient forebrain ischemia.
    Ann Neurol. 1982 May;11(5):491-8 PMID: 7103425
  31. A new generation of Ca2+ indicators with greatly improved fluorescence properties.
    J Biol Chem. 1985 Mar 25;260(6):3440-50 PMID: 3838314
  32. AMPA, but not NMDA, receptor antagonism is neuroprotective in gerbil global ischaemia, even when delayed 24 h.
    Eur J Pharmacol. 1993 Jun 4;236(3):347-53 PMID: 7689464
  33. RNA editing of glutamate receptor subunits GluR2, GluR5 and GluR6 in transient cerebral ischemia in the rat.
    J Cereb Blood Flow Metab. 1996 Jul;16(4):548-56 PMID: 8964793
  34. Neural apoptosis.
    Ann Neurol. 1995 Dec;38(6):839-51 PMID: 8526456
  35. Ca2+ permeability of KA-AMPA--gated glutamate receptor channels depends on subunit composition.
    Science. 1991 May 10;252(5007):851-3 PMID: 1709304
  36. Differences in Ca2+ permeability of AMPA-type glutamate receptor channels in neocortical neurons caused by differential GluR-B subunit expression.
    Neuron. 1994 Jun;12(6):1281-9 PMID: 8011338
  37. Differential expression of three glutamate receptor genes in developing rat brain: an in situ hybridization study.
    Proc Natl Acad Sci U S A. 1991 May 15;88(10):4157-61 PMID: 1851996
  38. Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS.
    Neuron. 1995 Jul;15(1):193-204 PMID: 7619522
  39. Selective dendrite damage in hippocampal CA1 stratum radiatum with unchanged axon ultrastructure and glutamate uptake after transient cerebral ischaemia in the rat.
    Brain Res. 1984 Jan 23;291(2):373-7 PMID: 6141837
  40. Switch in glutamate receptor subunit gene expression in CA1 subfield of hippocampus following global ischemia in rats.
    Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10499-503 PMID: 1438239
  41. Identification of a site in glutamate receptor subunits that controls calcium permeability.
    Science. 1991 Aug 30;253(5023):1028-31 PMID: 1653450
  42. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuroprotectant for cerebral ischemia.
    Science. 1990 Feb 2;247(4942):571-4 PMID: 2154034
  43. Micromolar Ca2+ transients in dendritic spines of hippocampal pyramidal neurons in brain slice.
    Neuron. 1995 Jun;14(6):1223-31 PMID: 7605633
  44. Heteromeric NMDA receptors: molecular and functional distinction of subtypes.
    Science. 1992 May 22;256(5060):1217-21 PMID: 1350383
  45. Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS.
    Science. 1990 Sep 28;249(4976):1580-5 PMID: 1699275
  46. NMDA and non-NMDA receptor gene expression following global brain ischemia in rats: effect of NMDA and non-NMDA receptor antagonists.
    J Neurochem. 1994 Mar;62(3):1067-73 PMID: 8113793
  47. Glutamate and the pathophysiology of hypoxic--ischemic brain damage.
    Ann Neurol. 1986 Feb;19(2):105-11 PMID: 2421636
  48. Delayed neuronal death in the gerbil hippocampus following ischemia.
    Brain Res. 1982 May 6;239(1):57-69 PMID: 7093691
  49. Cholinergic input uncouples Ca2+ changes from K+ conductance activation and amplifies intradendritic Ca2+ changes in hippocampal neurons.
    Neuron. 1991 Jun;6(6):901-5 PMID: 2054187
  50. Calcium: still center-stage in hypoxic-ischemic neuronal death.
    Trends Neurosci. 1995 Feb;18(2):58-60 PMID: 7537408
  51. Excitatory amino acid receptors and their role in epilepsy and cerebral ischemia.
    Ann N Y Acad Sci. 1995 May 10;757:492-505 PMID: 7611707
  52. Subunit composition at the single-cell level explains functional properties of a glutamate-gated channel.
    Neuron. 1994 Feb;12(2):383-8 PMID: 7509161
  53. Coordinated expression of messenger RNAs for nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the rat hippocampus following transient forebrain ischemia.
    Neuroscience. 1993 Jul;55(1):23-31 PMID: 8350988
  54. Selective vulnerability in the gerbil hippocampus following transient ischemia.
    Acta Neuropathol. 1984;62(3):201-8 PMID: 6695554
  55. Stress protein and proto-oncogene expression as indicators of neuronal pathophysiology after ischemia.
    Prog Brain Res. 1993;96:195-208 PMID: 8332741
  56. Acceleration of HSP70 and HSC70 heat shock gene expression following transient ischemia in the preconditioned gerbil hippocampus.
    J Cereb Blood Flow Metab. 1993 Sep;13(5):781-8 PMID: 8360284
  57. Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning.
    Proc Natl Acad Sci U S A. 1995 May 9;92(10):4666-70 PMID: 7753861
  58. The role of RNA editing in controlling glutamate receptor channel properties.
    J Neurochem. 1996 Jan;66(1):1-5 PMID: 8522940
  59. Molecular diversity of the NMDA receptor channel.
    Nature. 1992 Jul 2;358(6381):36-41 PMID: 1377365
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
0270-6474
Published
1997-08-15
Pages
6179-88
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6568367
Subset
IM
Grants
NINDS NIH HHS · NS 07512 · United States
NINDS NIH HHS · NS 20752 · United States
NINDS NIH HHS · NS 31282 · United States
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2