The role of immediate early genes in the stabilization of long-term potentiation

  • Wickliffe C. Abraham
  • Michael Dragunow
  • Warren P. Tate
Applied Aspects of Synaptic Plasticity


Immediate early genes (IEGs) are a class of genes that show rapid and transient but protein synthesisindependent increases in expression to extracellular signals such as growth factors and neurotransmitters. Many IEGs code for transcription factors that have been suggested to govern the growth and differentiation of many cell types by regulating the expression of other genes. IEGs are expressed in adult neurons both constitutively and in response to afferent activity, and it has been suggested that during learning, IEGs may play a role in the signal cascade, resulting in the expression of genes critical for the consolidation of long-term memory. Long-term potentiation (LTP) is a persistent activity-dependent form of synaptic plasticity that stands as a good candidate for the mechanism of associative memory. A number of IEGs coding for transcription factors have been shown to transiently increase transcription in the dentate gyrus of rats following LTP-inducing afferent stimulation. These includezif/268 (also termedNGFI-A, Krox-24, TIS-8, andegr-l),c-fos-related genes,c-jun, junB, and junD. Of these,zif/268 appears to be the most specifically related to LTP since it is evoked under virtually all LTP-inducing situations and shows a remarkably high correlation with the duration of LTP. There are a number of outstanding questions regarding the role ofzif/268 and other IEGs in LTP, including which second messenger systems are important for activating them, which “late effector” genes are regulated by them, and the exact role these genes play, if any, in the stabilization and maintenance of LTP.

Index Entries

Immediate early gene long-term memory long-term potentiation Northern blot immunohistochemistry hippocampus N-methyl-d-aspartate elongation factor-2 transcription factor 


  1. Abe H., Rusak B., and Robertson H. A. (1991) Photic induction offos protein in the suprachiasmatic nucleus is inhibited by the NMDA receptor antagonist MK-801.Neurosci. Lett. 127, 9–12.PubMedCrossRefGoogle Scholar
  2. Abraham W. C. (1988) Long-term potentiation as a possible associative memory mechanism in the brain.N. Z. J. Psych. 17, 49–58.Google Scholar
  3. Abraham W. C. and Goddard G. V. (1983) Asymmetric relations between homosynaptic long-term potentiation and heterosynaptic long-term depression.Nature 305, 717–719.PubMedCrossRefGoogle Scholar
  4. Abraham W. C. and Otani S. (1991) Macromolecules and the maintenance of long-term potentiation.Kindling and Synaptic Plasticity. Morrell F., ed., Birkhauser, Cambridge, MA.Google Scholar
  5. Abraham W. C. and Wickens J. R. (1991) Heterosynaptic long-term depression is facilitated by blockade of inhibition in area CA1 of the hippocampus.Brain Res. 546, 336–340.PubMedCrossRefGoogle Scholar
  6. Anokhin K. V. and Rose S. P. R. (1990) Learninginduced increase of immediate early gene messenger RNA in the chick forebrain.Eur. J. Neurosci. 3, 162–167.CrossRefGoogle Scholar
  7. Anokhin K. V., Mileusnic R., Shamkina I. Y., and Rose S. P. R. (1991) Effects of early experience on c-fos gene expression in the chick forebrain.Brain Res. 544, 101–107.PubMedCrossRefGoogle Scholar
  8. Auwerx J. and Sassone-Corsi P. (1991) IP-1: A dominant inhibitor offos/jun whose activity is modulated by phosphorylation.Cell 64, 983–993.PubMedCrossRefGoogle Scholar
  9. Barnes C. A. (1988) Spatial learning and memory processes: the search for their neurobiological mechanisms in the rat.Trends Neurosci. 11, 163–169.PubMedCrossRefGoogle Scholar
  10. Bartel D. P., Sheng M., Lau L. F., and Greenberg M. E. (1989) Growth factors and membrane depolarization activate distinct programs of early response gene expression: dissociation offos and jun induction.Genes Dev. 3, 304–313.PubMedCrossRefGoogle Scholar
  11. Bliss T. V. P. and Gardner-Medwin A. R. (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetised rabbit following stimulation of the perforant path.J. Physiol. 232, 357–374.PubMedGoogle Scholar
  12. Bliss T. V. P. and Lame T. (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetised rabbit following stimulation of the perforant path.J. Physiol. 232, 331–356.PubMedGoogle Scholar
  13. Bliss T. V. P. and Lynch M. A. (1988) Long-term potentiation of synaptic transmission in the hippocampus: properties and mechanisms.Long-term Potentiation: From Biophysics to Behavior. Deadwyler S. and Landfield P., eds., Liss, New York, pp. 3–72.Google Scholar
  14. Bullitt E. (1989) Induction of c-fos-like protein within the lumbar spinal cord and thalamus of the rat following peripheral stimulation.Brain Res. 493, 391–397.PubMedCrossRefGoogle Scholar
  15. Carter D. A. (1990) Temporally defined induction of c-fos in the rat pineal.Biochem. Biophys. Res. Comm. 166, 589–594.PubMedCrossRefGoogle Scholar
  16. Chang F.-L. and Greenough W. T. (1984) Transient and enduring morphological correlates of synaptic activity and efficacy change in rat hippocampal slice.Brain Res. 309, 35–46.PubMedCrossRefGoogle Scholar
  17. Changelian P. S., Feng P., King T. C., and Milbrandt J. (1989) Structure of the NGFI-A gene and detection of upstream sequences responsible for its transcriptional induction by nerve growth factor.Proc. Natl. Acad. Sci. USA 86, 377–381.PubMedCrossRefGoogle Scholar
  18. Chiu R., Boyle W. J., Meek J., Smeal T., Hunter T., and Karin M. (1988) The c-fos protein interacts with c-jun/AP-1 to stimulate transcription of AP-1 responsive genes.Cell 54, 541–552.PubMedCrossRefGoogle Scholar
  19. Christie B. R. and Abraham W. C. (in press) NMDA-dependent heterosynaptic long-term depression in the dentate gyrus of anaesthetized rats.Synapse.Google Scholar
  20. Christy B. and Nathans D. (1989) DNA binding site of the growth factor-inducible protein Zif268.Proc. Natl. Acad. Sci. USA 86, 8737–8741.PubMedCrossRefGoogle Scholar
  21. Christy B. A., Lau L. F., and Nathans D. (1988) A gene activated in mouse 3T3 cells by serum growth factors encodes a protein with “zinc. finger” sequences.Proc. Natl. Acad. Sci. USA 85, 7857–7861.PubMedCrossRefGoogle Scholar
  22. Cole A. J., Saffen D. W., Baraban J. M., and Worley P. F. (1989) Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation.Nature 340, 474–476.PubMedCrossRefGoogle Scholar
  23. Collingridge G. L., Kehl S. J., and McLennan H. (1983) Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.J. Physiol. 334, 33–46.PubMedGoogle Scholar
  24. Curran T. and Morgan J. I. (1985) Superinduction of c-fos by nerve growth factor in the presence of peripherally active benzodiazepines.Science 229, 1265–1268.PubMedCrossRefGoogle Scholar
  25. Curran T. and Morgan J. I. (1987) Memories offos.BioEssays 7, 255–258.PubMedCrossRefGoogle Scholar
  26. Dash P. K., Hochner B., and Kandel E. R. (1990) Injection of the cAMP-responsive element into the nucleus ofAplysia sensory neurons blocks longterm facilitation.Nature 345, 718–721.PubMedCrossRefGoogle Scholar
  27. Deadwyler S. A., Dunwiddie T., and Lynch G. (1987) A critical level of protein synthesis is required for long-term potentiation.Synapse 1, 90–95.PubMedCrossRefGoogle Scholar
  28. Desmond N. L. and Levy W. B. (1983) Synaptic correlates of associative potentiation/depression: an ultrastructural study in the hippocampus.Brain Res. 265, 21–30.PubMedCrossRefGoogle Scholar
  29. Doucet J. P., Squinto S. P., and Bazan N. G. (1990) Fos-Jun and the primary genomic response in the nervous system.Mol. Neurobiol. 2, 27–55.CrossRefGoogle Scholar
  30. Douglas R. M. and Goddard G. V. (1975) Long-term potentiation of the perforant path-granule cell synapse in the rat hippocampus.Brain Res. 86, 205–215.PubMedCrossRefGoogle Scholar
  31. Douglas R. M., Dragunow M., and Robertson H. A. (1988) High-frequency discharge of dentate granule cells, but not long-term potentiation, induces c-fos protein.Mol. Brain Res. 4, 259–262.CrossRefGoogle Scholar
  32. Dragunow M., Abraham W. C., Goulding M., Mason S. E., Robertson H. A., and Faull R. L. M. (1989) Long-term potentiation and the induction of c-fos mRNA and proteins in the dentate gyrus of unanesthetized rats.Neurosci. Lett. 101, 274–280.PubMedCrossRefGoogle Scholar
  33. Dragunow M. and Faull R. L. M. (1989) Rolipram induces c-fos protein-like immunoreactivity in ependymal and glial-like cells in adult rat brain.Brain Res. 501, 382–388.PubMedCrossRefGoogle Scholar
  34. Dragunow M. and Faull R. L. M. (1990) MK801 induces c-fos protein in thalamic and neocortical neurons of rat brain.Neurosci. Lett. 113, 144–150.PubMedCrossRefGoogle Scholar
  35. Dragunow M., Goulding M., Faull R. L. M., Ralph R., Mee E., and Frith R. (1990) Induction of c-fos mRNA and protein in neurons and glia after traumatic brain injury: pharmacological characterization.Exp. Neurol. 107, 236–248.PubMedCrossRefGoogle Scholar
  36. Dragunow M., Peterson M. R., and Robertson H. A. (1987) Presence of c-fos-like immunoreactivity in the adult rat brain.Eur. J. Pharmacol. 135, 113,114.CrossRefGoogle Scholar
  37. Dragunow M. and Robertson H. A. (1987) Kindling stimulation induces c-fos protein(s) in granule cells of the rat dentate gyrus.Nature 329, 441,442.CrossRefGoogle Scholar
  38. East S. J. and Garthwaite J. (1991) NMDA receptor activation in rat hippocampus induces cyclic GMP through the L-arginine nitric oxide pathway.Neurosci. Lett. 123, 17–19.PubMedCrossRefGoogle Scholar
  39. Frey U., Krug M., Brödemann R., Reymann K., and Matthies H. (1989) Long-term potentiation induced in dendrites separated from rat's CA1 pyramidal somata does not establish a late phase.Neurosci. Lett. 97, 135–139.PubMedCrossRefGoogle Scholar
  40. Goelet P., Castellucci V. F., Schacher S., and Kandel E. R. (1986) The long and the short of long-term memory—a molecular framework.Nature 322, 419–422.PubMedCrossRefGoogle Scholar
  41. Gonzalez G. A. and Montminy M. R. (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133.Cell 59, 675–680.PubMedCrossRefGoogle Scholar
  42. Greenberg M. E. and Ziff L. (1984) Stimulation of 3T3 cells induces transcription of thec-fos protooncogene.Nature 331, 433–437.CrossRefGoogle Scholar
  43. Greenberg M. E., Ziff E. B. and Greene L. A. (1986) Stimulation of neuronal acetylcholine receptors induces rapid gene transcription.Science 234, 80–83.PubMedCrossRefGoogle Scholar
  44. Gustafsson B., Wigström H., Abraham W. C., Huang Y.-Y. (1987) Long-term potentiation in the hippocampus using depolarizing current pulses as the conditioning stimulus to single volley synaptic potentials.J. Neurosci. 7, 774–780.PubMedGoogle Scholar
  45. Gustafsson B., Asztely F., Hanse E., and Wigström H. (1989) Onset characteristics of long-term potentiation in the guinea-pig hippocampal CA1 region in vitro.Eur. J. Neurosci. 1, 382–394.PubMedCrossRefGoogle Scholar
  46. Hendry I. A. (1973) Trans-synaptic regulation of tyrosine hydroxylase activity in a developing mouse sympathetic ganglion: effects of nerve growth factor (NGF), antiserum and pempidine.Brain Res. 56, 313–320.PubMedCrossRefGoogle Scholar
  47. Herdegen T., Walker T. Leah J. D., Bravo R., and Zimmerman M. (1990) The KROX-24 protein, a new transcription regulating factor: expression in the central nervous system following afferent somatosensory stimulation.Neurosci. Lett. 120, 21–24.PubMedCrossRefGoogle Scholar
  48. Hunt S. P., Pini A., and Evan G. (1987) Induction ofc-fos-like protein in spinal cord neurons following sensory stimulation.Nature 328, 632–634.PubMedCrossRefGoogle Scholar
  49. Jeffery K. J., Abraham W. C., Dragunow M., and Mason S. E. (1990) Induction offos-like immunoreactivity and the maintenance of long-term potentiation in the dentate gyrus of unanesthetized rats.Mol. Brain Res. 8, 267–274.PubMedCrossRefGoogle Scholar
  50. Krug M., Lössner B., and Ott T. (1984) Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats.Brain Res. Bull. 13, 39–42.PubMedCrossRefGoogle Scholar
  51. Kruijer W., Cooper J. A., Hunter T., and Verma I. M. (1984) Platelet-derived growth factor induces rapid but transient expression of thec-fos gene and protein.Nature 312, 711–716.PubMedCrossRefGoogle Scholar
  52. Lau L. F. and Nathans D. (1987) Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation withc-fos orc-myc.Proc. Natl. Acad. Sci. USA 84, 1182–1186.PubMedCrossRefGoogle Scholar
  53. Lee K. S., Schottler F., Oliver M., and Lynch G. (1980) Brief bursts of high-frequency stimulation produce two types of structural change in rat hippocampus.J. Neurophysiol. 44, 247–258.PubMedGoogle Scholar
  54. Lemaire P., Revelant O., Bravo R., and Charnay P. (1988) Two mouse genes encoding potential transcriptional factors with identical DNA-binding domains are activated by growth factors in cultured cells.Proc. Natl. Acad. Sci. USA 85, 4691–4695.PubMedCrossRefGoogle Scholar
  55. Levy W. B. and Steward O. (1979) Synapses as associative memory elements in the hippocampal formation.Brain Res. 175, 233–245.PubMedCrossRefGoogle Scholar
  56. Lovinger D. M., Akers R. F., Nelson R. B., Barnes C. A., McNaughton B. L., and Routtenberg A. (1985) A selective increase in phosphorylation of protein F1, a protein kinase C substrate, directly related to three day growth of long-term synaptic enhancement.Brain Res. 343, 137–143.PubMedCrossRefGoogle Scholar
  57. Lynch G. S., Dunwiddie T., and Gribkoff V. (1977) Heterosynaptic depression: a post-synaptic correlate of long-term potentiation.Nature 266, 737–739.PubMedCrossRefGoogle Scholar
  58. MacDermott A. B., Mayer M. L., Westbrook G. L., Smith S. J., and Barker J. L. (1986) NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones.Nature 321, 519–522.PubMedCrossRefGoogle Scholar
  59. Mack K., Day M., Milbrandt J., and Gottlieb D. I. (1990) Localization of the NGFI-A protein in the rat brain.Mol. Brain Res. 8, 177–180.PubMedCrossRefGoogle Scholar
  60. Matthies H. (1989) In search of cellular mechanisms of memory.Prog. Neurobiol. 32, 277–349.PubMedCrossRefGoogle Scholar
  61. Mayer M. L. and Miller R. J. (1990) Excitatory amino acid receptors, second messengers and regulation of infracellular Ca2+ in mammalian neurons.Trends Pharmacol. Sci. 11, 254–260.PubMedCrossRefGoogle Scholar
  62. Mellon P. L., Clegg C. H., Correll L. A. and McKnight G. S. (1989) Regulation of transcription by cyclic AMP-dependent protein kinase.Proc. Natl. Acad. Sci. USA 86, 4887–4891.PubMedCrossRefGoogle Scholar
  63. Mihaly A., Olah Z., Krug M., Kuhnt U., Matthies H., Rapp U. R., and Joo F. (1990) Transient increase ofraf protein kinase-like immunoreactivity in the rat dentate gyrus during long-term potentiation.Neurosci. Lett. 116, 45–50.PubMedCrossRefGoogle Scholar
  64. Morgan J. L., Cohen D. R., Hempstead J. L., and Curran T. (1987) Mapping patterns ofc-fos expression in the central nervous system after seizure.Science 237, 192–197.PubMedCrossRefGoogle Scholar
  65. Morgan J. I. and Curran T. (1986) Role of ion flux in the control ofc-fos expression.Nature 322, 552–555.PubMedCrossRefGoogle Scholar
  66. Morgan J. I. and Curran T. (1991) Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenesfos and jun.Ann. Rev. Neurosci. 14, 421–451.PubMedCrossRefGoogle Scholar
  67. Morris B. J., Feasey K. J., ten Bruggencate G., Herz A., and Hollt V. (1988) Electrical stimulationin vivo increases the expression of proenkephalin mRNA and decreases the expression of prodynorphin mRNA in rat hippocampal granule cells.Proc. Natl. Acad. Sci. USA 85, 3226–3230.PubMedCrossRefGoogle Scholar
  68. Müller R., Bravo R., Burckhardt J., and Curran T. (1984) Induction ofc-fos gene and protein by growth factors precedes activation ofc-myc.Nature 312, 716–720.PubMedCrossRefGoogle Scholar
  69. Nakabeppu Y., Ryder K., and Nathans D. (1988) DNA binding activities of three murine jun proteins: stimulation byfos.Cell 55, 907–915.PubMedCrossRefGoogle Scholar
  70. Nigg E. A., Hilz H., Eppenberger H. M., and Dutly F. (1985) Rapid and reversible translocation of the catalytic subunit of cAMP-dependent protein kinase type II from the Golgi complex to the nucleus.EMBO J. 86, 4887–4891.Google Scholar
  71. Olenik C., Lais A., and Meyer D. K. (1991) Effects of unilateral cortex lesions on gene expression of rat cortical cholecystokinin neurons.Mol. Brain Res. 10, 259–265.PubMedCrossRefGoogle Scholar
  72. Otani S., Marshall C. J., Tate W., Goddard G. V., Abraham W. C. (1989) Maintenance of long-term potentiation in rat dentate gyrus requires protein synthesis but not mRNA synthesis immediately post-tetanization.Neuroscience 28, 519–526.PubMedCrossRefGoogle Scholar
  73. Pavletich N. P. and Pabo C. O. (1991) Zinc finger-DNA recognition: crystal structure of azif268-DNA complex at 2.1 Ao.Science 252, 809–817.PubMedCrossRefGoogle Scholar
  74. Phillips L. L. and Steward O. (1990) Increases in mRNA for cytoskeletal proteins in the denervated neuropil of the dentate gyrus: anin situ hybridization study using riboprobes forB-actin andB-tubulin.Mol. Brain. Res. 8, 249–257.PubMedCrossRefGoogle Scholar
  75. Racine R. J., Milgram N. W., and Hafner S. (1983) Long-term potentiation phenomena in the rat limbic forebrain.Brain Res. 260, 217–232.PubMedCrossRefGoogle Scholar
  76. Richardson C. L., Tate W. P., Mason S. E., Lawlor P. A., Dragunow M., and Abraham W. C. (in press) Correlation between the induction of an immediate early gene,zif/268, and long-term potentiation in the dentate gyrus.Mol. Brain Res. Google Scholar
  77. Ryazanov A. G. (1987) Ca2+/calmodulin-dependent phosphorylation of elongation factor 2.FEBS Lett. 214, 331–334.PubMedCrossRefGoogle Scholar
  78. Ryazanov A. G. and Spirin A. S. (1990) Phosphorylation of elongation factor 2: a key mechanism regulating gene expression in vertebrates.New Biol. 2, 843–850.PubMedGoogle Scholar
  79. Ryder K. and Nathans D. (1988) Induction of protooncogenec-fos by serum growth factors.Proc. Natl. Acad. Sci. USA 85, 8464–8467.PubMedCrossRefGoogle Scholar
  80. Saffen D. W., Cole A. J., Worley P. F., Christy B. A., Ryder K., and Baraban J. M. (1988) Convulsantinduced increase in transcription factor messenger RNAs in rat brain.Proc. Natl. Acad. Sci. USA 85, 7795–7799.PubMedCrossRefGoogle Scholar
  81. Schlingensiepen K.-H., Lüno K., and Brysch W. (1991) High basal expression of thezif/268 immediate early gene in cortical layers IV and VI, in CA1 and in the corpus striatum—anin situ hybridization study.Neurosci. Lett. 122, 67–70.PubMedCrossRefGoogle Scholar
  82. Schreiber S. S., Tocco G., Shors T. J., and Thompson R. F. (1991) Activation of immediate early genes after acute stress.Neuro Report 2, 17–20.Google Scholar
  83. Sharp F. R., Gonzalez M. F., Sharp J. W., and Sagar S. M. (1989)c-fos expression and (14C) 2-deoxyglucose uptake in the caudal cerebellum of the rat during motor/sensory cortex stimulation.J. Comp. Neurol. 284, 621–636.PubMedCrossRefGoogle Scholar
  84. Sonnenberg J. L., Rauscher III F. J., Morgan J. I., and Curran T. (1989) Regulation of proenkephalin byfos and jun.Science 246, 1622–1625.PubMedCrossRefGoogle Scholar
  85. Sukhatme V. P., Cao X., Chang L. C., Tsai-Morris C.-H., Stamenkovich D., Ferreira P. C. P., Cohen D. R., Edwards S. A., Shows T. B., Curran T., Le Beau M. M., and Adamson E. D. (1988) A zinc fingerencoding gene coregulated withc-fos during growth and differentiation, and after cellular depolarization.Cell 53, 37–43.PubMedCrossRefGoogle Scholar
  86. Teyler T. J. and Discenna P. (1984) Long-term potentiation as a candidate mnemonic device.Brain Res. Rev. 7, 15–28.CrossRefGoogle Scholar
  87. Tippetts M. T., Varnum B. C., Lim R. W., and Herschman H. R. (1988) Tumor promoter-inducible genes are differentially expressed in the developing mouse.Mol. Cell. Biol. 8, 4570–4572.PubMedGoogle Scholar
  88. Tischmeyer W., Kaczmarek L., Strauss M., Jork R., and Matthies H. (1990) Accumulation ofc-fos mRNA in rat hippocampus during acquisition of a brightness discrimination.Behav. Neural Biol. 54, 165–171.PubMedCrossRefGoogle Scholar
  89. White J. D. and Gall C. M. (1987) Differential regulation of neuropeptide and proto-oncogene mRNA content in the hippocampus following recurrent seizures.Mol. Brain Res. 3, 21–29.CrossRefGoogle Scholar
  90. Wigström H., Gustafsson B., Huang Y.-Y. and Abraham W. C. (1986) Hippocampal long-term potentiation is induced by pairing single afferent volleys with intracellularly injected current pulses.Acta Physiol Scand. 126, 317–319.PubMedCrossRefGoogle Scholar
  91. Williams J. H., Errington M. L., Lynch M. A., and Bliss T. V. P. (1989) Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus.Nature 341, 739–742.PubMedCrossRefGoogle Scholar
  92. Wisden W., Errington M. L., Williams S., Dunnett S. B., Waters C., Hitchcock D., Evan, G., Bliss T. V. P., and Hunt S. P. (1990) Differential expression of immediate early genes in the hippocampus and spinal cord.Neuron 4, 603–614.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1991

Authors and Affiliations

  • Wickliffe C. Abraham
    • 1
    • 2
  • Michael Dragunow
    • 4
    • 2
  • Warren P. Tate
    • 3
    • 2
  1. 1.Department of PsychologyUniversity of OtagoDunedinNew Zealand
  2. 2.the Neuroscience Research CentreUniversity of OtagoDunedinNew Zealand
  3. 3.Department of BiochemistryUniversity of OtagoDunedinNew Zealand
  4. 4.Department of Pharmacology and Clinical PharmacologyUniversity of Auckland Medical SchoolDunedinNew Zealand

Personalised recommendations