Abstract
This article summarizes recent studies from the long-term potentiation (LTP), long-term depression (LTD), and behavioral learning literature, indicating that immediate-early genes (IEGs) may play an important role in learning and memory. The LTP studies suggest that synaptic modifications occurring during NMDA-receptor-mediated hippocampal LTP and LTD are stabilized by the protein products of the krox family of IEGs (as well as by brain-derived neurotrophic factor, BDNF). Activation of muscarinic receptors also induces members of the krox as well as the fos and jun family (jun-B but not c-jun) IEGs in hippocampal neurons and this action may be involved in the facilitatory effects of muscarinic receptor activation on both hippocampal LTP and learning. The possible role of IEGs in the learning-enhancing effects of cholinergically mediated hippocampal θ is also discussed. Finally, I review a number of recent studies showing IEG expression in brain neurons after behavioral learning. Together these results suggest some role for select IEGs (e.g., Krox 24) in learning and memory, although definitive studies using antisense DNA technology are required to establish any causal links. In particular, IEGs may be critical components of the signal transduction cascade that links NMDA and muscarinic receptors to the neuronal genome and ultimately to the generation of permanent modifications in neuronal biochemistry that provides the substrate for learning.
Similar content being viewed by others
References
Abraham, W. C., and Goddard, G. V. (1983). Asymmetric relationships between homosynaptic long-term potentiation and heterosynaptic long-term depression.Nature 305: 717–719.
Abraham, W. C., Dragunow, M., and Tate, W. P. (1991). The role of immediate early genes in the stabilization of long-term potentiation.Mol. Neurobiol. 5:297–314.
Abraham, W. C., Demmer, J., Richardson, C. L., Williams, J. M., Lawlor, P. A., Mason, S. E., Tate, W. P., and Dragunow, M. (1993). Correlations between immediate early gene induction and the persistence of LTP.Neuroscience 56:717–727.
Abraham, W., Christie, B., Logan, B., Lawlor, P., and Dragunow, M. (1994). Immediate-early gene expression associated with the persistence of heterosynaptic long-term depression in the hippocampus.Proc Natl Acad Sci USA 91:10049–10053.
Ambalavanar, R., Van der Zee, E. A., Bolhuis, J. J.,et al. (1993). Co-expression of Fos immunoreactivity in protein kinase (PKCγ)-positive neurones: Quantitative analysis of a brain region involved in learning.Brain Res. 606:315–318.
Anokhin, K. V., and Rose, S. P. R. (1990). Learning-induced increase of immediate early gene messenger RNA in the chick forebrain.Eur. J. Neurosci. 3:162–167.
Anokhin, K. V., Mileusnic, R., Shamakina, I. Y.,et al. (1991). Effects of early experience on c-fos gene expression in the chick forebrain.Brain Res. 544:101–107.
Bernard, V., Dumartin, B., Lamy, E.,et al. (1993). Fos immunoreactivity after stimulation or inhibition of muscarinic receptors indicates anatomical specificity for cholinergic control of striatal efferent neurons and cortical neurons in the rat.Eur. J. Neurosci. 5:1218–1225.
Bliss, T. V. P., and Collingridge, G. L. (1993). A synaptic model of memory: Long-term potentiation in the hippocampus.Nature 361:31–39.
Bliss, T. V. P., and Lomo, T. (1973). Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path.J. Physiol. 232:331–356.
Brennan, P. A., Hancock, D., and Keverne, E. B. (1992). The Expression of the immediate-early genes c-fos, egr-1 and c-jun in the accessory olfactory bulb during the formation of an olfactory memory in mice.Neuroscience 49:277–284.
Christy, B., and Nathans, D. (1989). Functional serum response elements upstream of the growth factor-inducible gene zif268.Mol. Cell. Biol. 9:4889–4895.
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.
Curran, T., and Morgan, J. I. (1987). Memories for fos.Bioessays 7:255–258.
Dash, P. K., Hochner, B., and Kandel, E. R. (1990). Injection of the cAMP-responsive element into the nucleus ofAplysia sensory neurons blocks long-term facilitation.Nature 345:718–721.
Demmer, J., Dragunow, M., Lawlor, P. A., Mason, S. E., Leah, J. D., Abraham, W. C., and Tate, W. P. (1993). Differential expression of Fos and Jun immediate early genes after hippocampal long-term potentiation in awake rats.Mol. Brain Res. 17:279–286.
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.
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.
Dragunow, M., Peterson, M. R., and Robertson, H. A. (1987). Presence of c-fos-like immunoreactivity in the adult rat brain.Eur. J. Pharm. 135:113–114.
Dragunow, M., Currie, R. W., Faull, R. L. M., Robertson, H. A., and Jensen, K. (1989a). Immediate-early genes, kindling and long-term potentiation.Neurosci. Behav. Rev. 24:301–313.
Dragunow, M., Abraham, W. C., Goulding, M., Mason, S. E., Robertson, H. A., and Faull, R. L. M. (1989b). Long-term potentiation and the induction of c-fos mRNA and protein in the dentate gyrus of unanaesthetized rats.Neurosci. Lett. 101:274–280.
Dragunow, M., Beilharz, E., Mason, B.,et al. (1993). Brain-derived neurotrophic factor expression after long-term potentiation.Neurosci. Lett. 160:232–236.
Dragunow, M., Lawlor, P., Chiasson, B.,et al. (1993). C-fos antisense generates apomorphine- and amphetamine-induced rotation.Neuroreport 5:305–306.
Falkenberg, T., Mohammed, A. K., Henriksson, B.,et al. (1992). Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment.Neurosci. Lett. 138:153–156.
Frey, U., Huang, Y.-Y., and Kandel, E. R. (1993). Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons.Science 260:1661–1664.
Heurteaux, C., Messier, C., Destrade, C.,et al. (1993). Memory processing and apamin induce immediate early gene expression in mouse brain.Mol. Brain Res. 18:17–22.
Holford, N. H. G., and Peace, K. E. (1992). Results and validation of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine.Proc. Natl. Acad. Sci. USA 89:11471–11475.
Huerta, P. T., and Lisman, J. E. (1993). Heightened synaptic plasticity of hippocampal CA1 neurons during a cholinergically induced rhythmic state.Nature 364:723–725.
Hughes, P., and Dragunow, M. (1993). Muscarinic receptor-mediated induction of Fos protein in rat brain.Neurosci. Lett. 150:122–126.
Hughes, P., Beilharz, E., Gluckman, P.,et al. (1993b). Brain-derived neurotrophic factor is induced as an immediate-early gene following N-methyl-D-aspartate receptor activation.Neuroscience 57:319–328.
Hughes, P., and Dragunow, M. (1994). Activation of pirenzepine-sensitive muscarinic receptors induces a specific pattern of immediate-early gene expression in rat brain neurons.Mol. Brain Res. 24:166–178.
Hughes, P., Dragunow, M., Beilharz, E., Lawlor, P., and Gluckman, P. (1993a). MK801 induces immediate-early gene proteins and BDNF mRNA in rat cerebrocortical neurons.Neuroreport 4:183–186.
Irwin, K. B., Craig, A. D., Bracha, V.,et al. (1992). Distribution of c-fos expression in brainstem neurons associated with conditioning and pseudo-conditioning of the rabbit nictitating membrane reflex.Neurosci. Lett. 148:71–75.
Jansen, K. L. R., Faull, R. L. M., Dragunow, M.,et al. (1990). Alzheimer's disease: Changes in hippocampal N-methyl-D-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opiod receptors—an autoradiographic study.Neuroscience 39:613–627.
Jeffery, K. J., Abraham, W. C., Dragunow, M., and Mason, S. E. (1990). Induction of Fos-like immunoreactivity and the maintenance of long-term potentiation in the dentate gyrus of unanaesthetized rats.Mol. Brain Res. 8:267–274.
Lemaire, P., Revelant, O., Bravo, R., and Charnay, P. (1988). Two mouse genes encoding potential transcription factors with identical DNA-binding domains are activated by growth factors in cultured cells.Proc. Natl. Acad. Sci. USA 85:4691–4695.
Leone, P., Dragunow, M., Davis, K. E., Ullrey, D.,et al. (1993). Hippocampal injection of a HSV-1 vector expressing an unregulated PKC from the TH promotor increases NE release, induces Krox 24 expression in dentate granule cells and improves spatial navigation performance in rats.Soc. Neurosci. Abstr. 19:806.
Lin, Y., and Phillis, J. W. (1991). Muscarinic agonist-mediated induction of long-term potentiation in rat cerebral cortex.Brain Res. 551:342–345.
Matthies, H. (1989). In search of cellular mechanisms of memory.Prog. Neurobiol. 32:277–349.
Mello, C. V., Vicario, D. S., and Clayton, D. F. (1992). Song presentation induces gene expression in the songbird forebrain.Proc. Natl. Acad. Sci. USA 89:6818–6822.
Morgan, J. I., Cohen, D. R., Hempstead, J. L.,et al. (1987). Mapping patterns of c-fos expression in the central nervous system after seizure.Science 237:192–197.
Morgan, J. I., and Curran, T. (1991). Stimulus-transcription coupling in the nervous system: Involvement of the inducible proto-oncogenes fos and jun.Annu. Rev. Neurosci. 14:421–451.
Nakazawa, K., Karachot, L., Nakabeppu, Y.,et al. (1993). The conjunctive stimuli that cause long-term desensitization also predominantly induce c-Fos and Jun-B in cerebellar Purkinje cells.Neuroreport 4:1275–1278.
Nikolaev, E., Tischmeyer, W., Krug, M., Matthies, H., and Kaczmarek, L. (1991). c-fos protooncogene expression in rat hippocampus and entorhinal cortex following tetanic stimulation of the perforant path.Brain Res. 560:346–350.
Nikolaev, E., Kaminska, B., Tischmeyer, W.,et al. (1992a). Induction of expression of genes encoding transcription factors in the rat brain elicited by behavioural training.Brain Res. Bull. 28:479–484.
Nikolaev, E., Werka, T., and Kaczmarek, L. (1992b). C-fos protooncogene expression in rat brain after long-term training of two-way active avoidance reaction.Behav. Brain Res. 48:91–94.
Ohno, M., Yamamoto, T., and Watanabe, S. (1992). Effects of intrahippocampal injections of NMDA receptor antagonists and scopolamine on working and reference memory assessed in rats by three-panel runway task.J. Pharmacol. Exp. Ther. 263:943–950.
Otani, S., Marshal, C. J., Tate, W. P.,et al. (1989). Maintenance of long-term potentiation in rat dentate gyrus requires protein synthesis but not messenger RNA synthesis immediately post-tetanization.Neuroscience 28:519–526.
Phillips, H. S., Hains, J. M., Armanini, M., Laramee, G. R., Johnson, S. A., and Winslow, J. W. (1992). BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease.Neuron 7:695–702.
Pombo-Villar, E., Wiederhold, K.-H., Mengod, G.,et al. (1992). Stereoisomerism and muscarinic receptor agonists: Synthesis and effects of the stereoisomers of 3-[5-(3-amino-1,2,4-oxadiazol)yl]-1-azabicyclo [2.2.1] heptane.Eur. J. Pharm. 226:317–325.
Qian, Z., Gilbert, M. E., Colicos, M. A., Kandel, E. R., and Kuhl, D. (1993). Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation.Nature 361:453–457.
Richardson, C. L., Tate, W. P., Mason, S. E., Lawlor, P. A., Dragunow, M., and Abraham, W. C. (1992). Correlation between the induction of an immediate early gene, zif/268, and long-term potentiation in the dentate gyrus.Brain Res. 580:147–154.
Rose, S. P. R. (1991). How chicks make memories: The cellular cascade from c-fos to dendritic remodelling.Trends Neurosci. 14:390–397.
Schreiber, S. S., Maren, S., Tocco, G., Shors, T. J., and Thompson, R. F. (1991). A negative correlation between the induction of long-term potentiation and activation of immediate early genes.Mol. Brain Res. 11:89–91.
Sheng, M., and Greenberg, M. E. (1990). The regulation and function of c-fos and other immediate early genes in the nervous system.Neuron 4:477–485.
Tischmeyer, W., Kaczmarek, L., Strauss, M.,et al. (1990). Accumulation of c-fos mRNA in rat hippocampus during acquisition of a brightness discrimination.Behav. Neural Biol. 54:165–171.
Wetmore, C., Cao, Y., Petterson, R. F.,et al. (1991). Brain-derived neurotrophic factor: Subcellular compartmentalization and interneuronal transfer as visualized with anti-peptide antibodies.Proc. Natl. Acad. Sci. USA 88: 9843–9847.
Wickens, J. R., and Abraham, W. C. (1991). The involvement of L-type calcium channels in heterosynaptic long-term depression in the hippocampus.Neurosci. Lett. 130:128–132.
Williams, J., Lawlor, P., Mason, B., Abraham, W., Leah, J., Bravo, R., Demmer, J., Tate, W., and Dragunow, M. (1995). Krox 20 may play a key role in the stabilization of long-term potentiation.Mol. Brain Res. 28:87–93.
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.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dragunow, M. A role for immediate-early transcription factors in learning and memory. Behav Genet 26, 293–299 (1996). https://doi.org/10.1007/BF02359385
Issue Date:
DOI: https://doi.org/10.1007/BF02359385