Amino Acids

, Volume 7, Issue 3, pp 245–254 | Cite as

Glutamate-evoked gene expression in brain cells — Focus on transcription factors

  • L. Kaczmarek
Review Article


L-glutamate (L-glu) is major excitatory neurotransmitter in mammalian central nervous system. Besides short term effects on neuronal activity, L-glu affects also long term neuronal and glial responses. Neuromodulatory function of L-glu may in part be dependent on its ability to activate transcription factors — proteins regulating gene expression through interaction with specific regulatory sequences located in promoter and enhancer gene regions. This paper reviews recent data suggesting that L-glu can selectively stimulate genes encoding transcription factors like zif/268 and fos and jun gene families, as well as the factors themselves both in neurons and astroglia cultured in vitro and brain cells in vivo.


Amino acids AP-1 c-fos c-jun zif/268 NGF-IA egr-1 krox-24 NMDA Neurons Glia Neural plasticity Excitatory amino acids 


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  1. Abe H, Rusak B, Robertson HA (1991) Photic induction of Fos protein in the suprachiasmatic nucleus is inhibited by the NMDA receptor antagonist MK-801. Neurosci Lett 127: 9–12Google Scholar
  2. Abe H, Rusak B, Robertson HA (1992) NMDA and non-NMDA receptor antagonists inhibit photic induction of Fos protein in the hamster suprachiasmatic nucleus. Brain Res Bull 28: 831–835Google Scholar
  3. Angel P, Karin M (1991) The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochem Biophys Acta 1072: 129–157Google Scholar
  4. Bading H, Ginty DD, Greenberg ME (1993) Regulation of gene expression in hippocampal neurons by distinct calcium signalling pathways. Science 260: 181–186Google Scholar
  5. Baeuerle PA (1991) The inducible transcription factors NF-κB: regulation by distinct protein subunits. Biochim Biophys Acta 1072: 63–80Google Scholar
  6. Bliss TVP, Lomo TJ (1973) Long lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol (London) 232: 331–356Google Scholar
  7. Collingridge GL, Singer W (1990) Excitatory amino acid receptors and synaptic plasticity. Trends Pharmacol Sci 11: 290–296Google Scholar
  8. Colotta F, Polentarutti N, Sironi M, Mantovani A (1992) Expression and involvement ofc-fos andc-jun protooncogenes in programmed cell death induced by growth factor deprivation in lymphoid cell lines. J Biol Chem 267: 18278–18283Google Scholar
  9. Condorelli DF, Dell'Albani P, Amico C, Kaczmarek L, Nicoletti F, Lukasiuk K, Giuffrida-Stella AM (1993) Induction of primary response genes by excitatory amino acids receptor agonists in primary astroglial cultures. J Neurochem 60: 877–885Google Scholar
  10. Condorelli DF, Kaczmarek L, Nicoletti F, Arcidiacono A, Dell'Albani P, Ingrao F, Magri G, Malaguarnera L, Avola R, Messina A, Giuffrida Stella AM (1989) Induction of protooncogene c-fos by extracellular signals in primary astroglial cell cultures. J Neurosci Res 23: 234–239Google Scholar
  11. Curran T, Morgan JI (1987) Memories of fos. BioEssays 7: 255–258Google Scholar
  12. Didier M, Roux P, Piechaczyk M, Verrier B, Bockaert J, Pin J-P (1989) Cerebellar granule cell survival and maturation induced by K+ and NMDA correlate with c-fos proto-oncogene expression. Neurosci Lett 107: 55–62Google Scholar
  13. Didier M, Roux P, Piechaczyk M, Mangeat P, Devilliers G, Bockaert J, Pin J-P (1992) Long-term expression of thec-fos protein during the in vitro differentiation of cerebellar granule cells induced by potassium or NMDA. Mol Brain Res 12: 249–258Google Scholar
  14. Demmer J, Dragunow M, Lawror PA, Mason SE, Leah JD, Abraham WC, Tate WP (1993) Differential expression of immediate early genes after hippocampal long-term potentiation in awake rats. Mol Brain Res 17: 279–286Google Scholar
  15. Dragunow M, Faull RLM (1990) MK-801 inducesc-fos protein in thalamic and neocortical neurons in rat brain. Neurosci Lett 111: 39–45Google Scholar
  16. Dragunow M, Abraham WC, Goulding M, Mason SE, Roberson HA, Faull RLM (1989) Long-term potentiation and the induction ofc-fos mRNA and proteins in the dentate gyrus of unanesthetized rats. Neurosci Lett 101: 274–280Google Scholar
  17. Dragunow M, Young D, Hughes P, MacGibbon G, Lawlor P, Singleton K, Sirimanne E, Beilharz E, Gluckman P (1993) Is c Jun involved in nerve cell death following status epilepticus and hypoxic-ischaemic brain injury? Mol Brain Res 18: 347–352Google Scholar
  18. Gass P, Herdegen T, Bravo R, Kiessling M (1993) Induction and suppresion of immediate early genes in specific rat brain regions by the non-competitive N-methylD-aspartate receptor antagonist MK-801. Neuroscience 53: 749–758Google Scholar
  19. Goelet P, Castelluci VF, Schacher S, Kandel ER (1986) The long and the short of long term memory — a molecular framework. Nature (London) 322: 419–423Google Scholar
  20. Gunn AJ, Dragunow M, Faull RLM, Gluckman PD (1990) Effects of hypoxia-ischemia and seizures on neuronal and glial-likec-fos protein levels in the infant rat. Brain Res 531: 105–116Google Scholar
  21. Guthrie KM, Anderson AJ, Leon M, Gall C (1993) Odor-induced increases in c-fos mRNA expression reveal an anatomical “unit” for odor processing in olfactory bulb. Proc Natl Acad Sci USA 90: 3329–3333Google Scholar
  22. Heilig M, Engel JA, Soderpalm B (1993) C-fos antisense in the nucleus accumbens blocks the locomotor stimulant action of cocaine. Eur J Pharmacol 236: 339–340Google Scholar
  23. Hisanaga K, Sagar SM, Sharp FR (1992) N-methyl-D-aspartate antagonists block Fos-like protein expression induced via multiple signalling pathways in cultured cortical neurons. J Neurochem 58: 1836–1844Google Scholar
  24. Jensen FE, Firkusny IR, Mower GD (1993) Differences in c-fos immunoreactivity due to age of seizure induction. Mol Brain Res 17: 185–193Google Scholar
  25. Kaczmarek L (1986) Protooncogene expression during the cell cycle. Lab Invest 54: 365–377Google Scholar
  26. Kaczmarek L (1993a) Glutamate receptor-driven gene expression in learning. Acta Neurobiol Exp 53: 187–196Google Scholar
  27. Kaczmarek L (1993b) Molecular biology of vertebrate learning: isc-fos a new beginning? J Neurosci Res 34: 377–381Google Scholar
  28. Kaczmarek L, Kaminska B (1989) Molecular biology of cell activation. Exp Cell Res 183: 24–35Google Scholar
  29. Kaczmarek L, Siedlecki JA, Danysz W (1988) Proto-oncogenec-fos induction in rat hippocampus. Mol Brain Res 3: 188–186Google Scholar
  30. Le Gal La Salle G (1988) Long-lasting and sequential increase ofc-fos oncoprotein expression in kainic acid induced status epilepticus. Neurosci Lett 88: 127–130Google Scholar
  31. Lerea LS, Butler LS, McNamara JO (1992) NMDA and non-NMDA receptor-mediated increase ofc-fos mRNA in dentate gyrus neurons involves calcium influx via different routes. J Neurosci 12: 2973–2981Google Scholar
  32. Lerea LS, Mcnamara JO (1993) Ionotropic glutamate receptor subtypes activatec-fos transcription by distinct calcium-requiring intracellular signalling pathways. Neuron 10: 31–41Google Scholar
  33. McNaughton LA, Hunt SP (1993) Regulation of gene expression in astrocytes by excitatory amino acids. Mol Brain Res 16: 261–266Google Scholar
  34. Montminy MR, Gonzales GA, Yamamoto KK (1990) Regulation of cAMP-inducible genes by CREB. Trends Neurosci 13: 184–188Google Scholar
  35. Morgan JI, Curran T (1991a) Stimulus-transcription coupling in the nervous system: involvement of the inducible protooncogenes fos and jun. Annu Rev Neurosci 14: 421–451Google Scholar
  36. Morgan JI, Curran T (1991b) Proto-oncogene transcription factors and epilepsy. Trends Pharmacol Sci 12: 343–349Google Scholar
  37. Morgan PF, Linnoila M (1991) Regional induction ofc-fos mRNA by NMDA: a quantitative in-situ hybridization study. NeuroReport 2: 251–254Google Scholar
  38. Murphy TH, Worley PF, Nakabeppu Y, Christy B, Gastel J, Baraban JM (1991a) Synaptic regulation of immediate early gene expression in primary cultures of cortical neurons. J Neurochem 57: 1862–1872Google Scholar
  39. Murphy TH, Worley PF, Baraban JM (1991b) L-type voltage- sensitive calcium channels mediate synaptic activation of immediate early genes. Neuron 7: 625–635Google Scholar
  40. Nedivi E, Hevroni D, Naot D, Israeli D, Citri Y (1993) Numerous candidate plasticity-related genes revealed by differential cDNA cloning. Nature 363: 718–722Google Scholar
  41. Nitsch R, Frotscher M (1992) Reduction of posttraumatic transneuronal “early gene” activation and dendritic atrophy by the N-methyl-D-aspartae receptor antagonist MK-801. Proc Natl Acad Sci USA 89: 5197–5200Google Scholar
  42. Nozaki K, Beal MF (1992) Neuroprotective effects of L-kynurenine on hypoxia-ischemia and NMDA lesions in neonatal rats. J Cereb Blood Flow Metab 12: 400–407Google Scholar
  43. Pennypacker KR, Walczak D, Thai L, Fannin R, Mason E, Douglass J, Hong JS (1993) Kainate-induced changes in opioid peptide genes and AP-1 protein expression in rat hippocampus. J Neurochem 60: 204–211Google Scholar
  44. Popovici T, Represa A, Crepel V, Barbin G, Beauoin M, Ben-Ari Y (1990) Effects of kainic acid-induced seizures and ischemia on c-fos-like proteins in rat brain. Brain Res 536: 183–194Google Scholar
  45. Riabowol K, Schiff J, Gilman MZ (1992) Transcription factor AP-1 activity is required for initiation of DNA synthesis and is lost during cellular aging. Proc Natl Acad Sci (USA) 89: 157–161Google Scholar
  46. Sakurai H, Kurusu R, Sano K, Tsuchiya T, Tsuda M (1992) Stimulation of cultured cerebellar granule cells via glutamate receptors induces TRE-and CRE-binding activities mediated by common DNA-binding complexes. J Neurochem 59: 2067–2075Google Scholar
  47. Sakurai-Yamashita Y, Sassone-Corsi P, Gombos G(1991) Immunohistochemistry of c-fos in mouse brain during postnatal development: basal levels and changing response to metrazol and kainate injection. Eur J Neurosci 3: 764–770Google Scholar
  48. Sheng M, Greenberg ME (1990) The regulation of function of c-fos and other immediately early genes in the nervous system. Neuron 4: 477–485Google Scholar
  49. Smeyne RJ, Schilling K, Robertson L, Luk D, Oberdick J, Curran T, Morgan JI (1992) Fos-lacZ transgenic mice: mapping sites of gene induction in the central nervous system. Neuron 8: 13–23Google Scholar
  50. Smeyne RJ, Vendrell M, Hayward M, Baker SJ, Miao GG, Schilling K, Robertson LM, Curran T, Morgan JI (1993) Continuousc-fos expression precedes programmed cell death in vivo. Nature 363: 166–169Google Scholar
  51. Sonnenberg JL, Mitchelmore C, Macgregor-Leon PF, Hempstead J, Morgan JI, Curran T (1989) Glutamate receptor agonists increase the expression of Fos, Fra and AP-1 DNA binding activity in the mammalian brain. J Neurosci Res 24: 72–80Google Scholar
  52. Szekely AM, Barbacia ML, Costa E (1987) Activation of specific glutamate receptors increasesc-fos proto-oncogene expression in primary cultures of neonatal rat cerebellar granule cells. Neuropharmacology 26: 1779–1787Google Scholar
  53. Szekely AM, Barbacia ML, Alho H, Costa E (1989) In primary cultures of cerebellar granule cells the activation of N-methyl-D-aspartate-sensitive glutamate receptors inducesc-fos mRNA expression. Mol Pharmacol 35: 401–408Google Scholar
  54. Vaccarino FM, Hayward MD, Nestler EJ, Duman RS, Tallman JF (1991) Differential induction of immediate early genes by excitatory amino acid receptors types in primary cultures of cortical and striatal neurons. Mol Brain Res 12: 233–241Google Scholar
  55. Worley PF, Cole AJ, Murphy TH, Christy BA, Nakabeppu Y, Baraban JM (1990) Synaptic regulation of immediate-early genes in brain. Cold Spring Harbor Symp Quant Biol 40: 213–223Google Scholar
  56. Worley P, Christy BA, Nakabeppu Y, Bhat RV, Cole AJ, Baraban JM (1991) Constitutive expression ofzif/268 in neocortex is regulated by synaptic activity. Proc Natl Acad Sci USA 88: 5106–5110Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • L. Kaczmarek
    • 1
  1. 1.Nencki Institute of Experimental BiologyWarsawPoland

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