Abstract
The facilitation of hippocampus-based, long-lasting synaptic plasticity, which is frequently investigated in model systems such as long-term potentiation (LTP) and in learning paradigms such as the Morris water maze, is associated with several cellular key events: Ca2+ influx through the n-methyl-d-aspartate (NMDA) receptor, generation of cyclic AMP (cAMP) and activation of protein kinase A (PKA), phosphorylation of mitogen-associated protein kinase (MAPK) and cAMP-response element-binding protein (CREB), and subsequent transcription of plasticity-associated genes.
Recently, a signal-transduction cascade from cAMP/PKA to MAPK was discovered, which seems to be neuron-specific and comprises the critical events of hippocampus-based long-term plasticity described here into one single cascade. A major alternative to cAMP/PKA-MAPK signaling are the cascades from Ca2+ to MAPK via Ras. However, Ras is inhibited by PKA. This article reviews the studies that argue for the existence of two competing pathways, and discusses their implication for the molecular mechanisms underlying synaptic plasticity.
Similar content being viewed by others
References
Milner B., Squire L. R., and Kandel E. R. (1998) Cognitive neuroscience and the study of memory. Neuron 20, 445–468.
Silva A. J. and Giese K. P. (1994) Plastic genes are in! Curr. Opin. Neurobiol. 4, 413–420.
Bliss T. V. 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.
Bliss T. V. and Collingridge G. L. (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39.
Morris R. G., Garrud P., Rawlins J. N., and O’Keefe J. (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683.
Lynch G., Larson J., Kelso S., Barrionuevo G., and Schottler F. (1983) Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature 305, 719–721.
Davis S., Butcher S. P., and Morris R. G. (1992) The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. J. Neurosci. 12, 21–34.
Abel T., Nguyen P. V., Barad M., Deuel T. A., Kandel E. R., and Bourtchouladze R. (1997) Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88, 615–626.
Huang Y. Y., Li X. C., and Kandel E. R. (1994) cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase. Cell 79, 69–79.
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.
Bartsch D., Ghirardi M., Skehel P. A., Karl K. A., Herder S. P., Chen M., et al. (1995) Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 83, 979–992.
Yin J. C., Del Vecchio M., Zhou H., and Tully T. (1995) CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 81, 107–115.
Yin J. C., Wallach J. S., Del Vecchio M., Wilder E. L., Zhou H., Quinn W. G., et al. (1994) Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79, 49–58.
Dash P. K., Hochner B., and Kandel E. R. (1990) Injection of the cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature 345, 718–721.
Bourtchuladze R., Frenguelli B., Blendy J., Cioffi D., Schutz G., and Silva A. J. (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79, 59–68.
Pittenger C., Huang Y. Y., Paletzki R. F., Bourtchouladze R., Scanlin H., Vronskaya S., et al. (2002) Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron 34, 447–462.
English J. D. and Sweatt J. D. (1996) Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation. J. Biol. Chem. 271, 24,329–24,332.
English J. D. and Sweatt J. D. (1997) A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J. Biol. Chem. 272, 19,103–19,106.
Atkins C. M., Selcher J. C., Petraitis J. J., Trzaskos J. M., and Sweatt J. D. (1998) The MAPK cascade is required for mammalian associative learning. Nat. Neurosci. 1, 602–609.
Selcher J. C., Atkins C. M., Trzaskos J. M., Paylor R., and Sweatt J. D. (1999) A necessity for MAP kinase activation in mammalian spatial learning. Learn. Mem. 6, 478–490.
Blum S., Moore A. N., Adams F., and Dash P. K. (1999) A mitogen-activated protein kinase cascade in the CA1/CA2 subfield of the dorsal hippocampus is essential for long-term spatial memory. J. Neurosci. 19, 3535–3544.
Impey S., Obrietan K., Wong S. T., Poser S., Yano S., Wayman G., et al. (1998) Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21, 869–883.
Sweatt J. D. (2001) Protooncogenes subserve memory formation in the adult CNS. Neuron 31, 671–674.
Vossler M. R., Yao H., York R. D., Pan M. G., Rim C. S., and Stork P. J. (1997) cAMP activates MAP kinase and Elk-1 through a B-Raf-and Rap1-dependent pathway. Cell 89, 73–82.
Grewal S. S., Fass D. M., Yao H., Ellig C. L., Goodman R. H., Stork P. J., et al. (2000) Calcium and cAMP signals differentially regulate cAMP-responsive element-binding protein function via a Rap1-extracellular signal-regulated kinase pathway. J. Biol. Chem. 275, 34,433–34,441.
Grewal S. S., Horgan A. M., York R. D., Withers G. S., Banker G. A., and Stork P. J. (2000) Neuronal calcium activates a Rap1 and B-Raf signaling pathway via the cyclic adenosine monophosphate-dependent protein kinase. J. Biol. Chem. 275, 3722–3728.
Kim S., Mizoguchi A., Kikuchi A., and Takai Y. (1990) Tissue and subcellular distributions of the smg-21/rap1/Krev-1 proteins which are partly distinct from those of c-ras p21s. Mol. Cell. Biol. 10, 2645–2652.
Beranger F., Goud B., Tavitian A., and de Gunzburg J. (1991) Association of the Ras-antagonistic Rap1/Krev-1 proteins with the Golgi complex. Proc. Natl. Acad. Sci. USA 88, 1606–1610.
Barnier J. V., Papin C., Eychene A., Lecoq O., and Calothy G. (1995) The mouse B-raf gene encodes multiple protein isoforms with tissue-specific expression. J. Biol. Chem. 270, 23,381–23,389.
Morice C., Nothias F., Konig S., Vernier P., Baccarini M., Vincent J. D., et al. (1999) Raf-1 and B-Raf proteins have similar regional distributions but differential subcellular localization in adult rat brain. Eur. J. Neurosci. 11, 1995–2006.
Thomas K. L., Laroche S., Errington M. L., Bliss T. V., and Hunt S. P. (1994) Spatial and temporal changes in signal transduction pathways during LTP. Neuron 13, 737–745.
Morozov A., Bourtchuladze R., Lapidus K., Gordon R., van Strien N., and Kandel E. R. (1999) Rap1, a possible coupling signal between the cAMP/PKA and MAPK cascade, is required for spatial learning in mice. Soc. Neurosci. Abstr. 25, 255.1.
Muzzio I. A., Morozov A., Winder D. G., and Kandel E. R. (2000) The cAMP-activated small GTPase Rap1 provides dual regulation of the MAP kinase cascade and is critical for plasticity in the hippocampal area CA1. Soc. Neurosci. Abstr. 26, 133.3.
Chen A. P., Giese K. P., Ono M., and Silva A. J. (1999) B-Raf plays a role in learning and memory. Soc. Neurosci. Abstr. 25, 256.10.
Chen A. P., Ohno M., and Silva A. J. (2000) B-Raf knock-out mice show deficits in hippocampal-dependent learning & LTP and decreased MAPK phosphorylation. Soc. Neurosci. Abstr. 26, 564.9.
Brambilla R., Gnesutta N., Minichiello L., White G., Roylance A. J., Herron C. E., et al. (1997) A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390, 281–286.
Roberson E. D., English J. D., Adams J. P., Selcher J. C., Kondratick C., and Sweatt J. D. (1999) The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J. Neurosci. 19, 4337–4348.
Abeliovich A., Paylor R., Chen C., Kim J. J., Wehner J. M., and Tonegawa S. (1993) PKC gamma mutant mice exhibit mild deficits in spatial and contextual learning. Cell 75, 1263–1271.
Abeliovich A., Chen C., Goda Y., Silva A. J., Stevens C. F., and Tonegawa S. (1993) Modified hippocampal long-term potentiation in PKC gamma-mutant mice. Cell 75, 1253–1262.
Malinow R., Schulman H., and Tsien R. W. (1989) Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science 245, 862–866.
Frankland P. W., O’Brien C., Ohno M., Kirkwood A., and Silva A. J. (2001) Alpha-CaMKII-dependent plasticity in the cortex is required for permanent memory. Nature 411, 309–313.
Chen H. J., Rojas-Soto M., Oguni A., and Kennedy M. B. (1998) A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20, 895–904.
Kim J. H., Liao D., Lau L. F., and Huganir R. L. (1998) SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 20, 683–691.
Costa R. M., Federov N. B., Kogan J. H., Murphy G. G., Stern J., Ohno M., et al. (2002) Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 526–530.
Silva A. J., Frankland P. W., Marowitz Z., Friedman E., Lazlo G., Cioffi D., et al. (1997) A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat. Genet. 15, 281–284.
Deisseroth K., Bito H., and Tsien R. W. (1996) Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16, 89–101.
Davis S., Vanhoutte P., Pages C., Caboche J., and Laroche S. (2000) The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J. Neurosci. 20, 4563–4572.
Kang H., Sun L. D., Atkins C. M., Soderling T. R., Wilson M. A., and Tonegawa S. (2001) An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell 106, 771–783.
Dragunow M., Abraham W. C., Goulding M., Mason S. E., Robertson H. A., and Faull R. L. (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.
Waltereit R., Dammermann B., Wulff P., Scafidi J., Staubli U., Kauselmann G., et al. (2001) Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation. J. Neurosci. 21, 5484–5493.
Worley P. F., Bhat R. V., Baraban J. M., Erickson C. A., McNaughton B. L., Barnes C. A., et al. (1993) Thresholds for synaptic activation of transcription factors in hippocampus: correlation with long-term enhancement. J. Neurosci. 13, 4776–4786.
Link W., Konietzko U., Kauselmann G., Krug M., Schwanke B., Frey U., et al. (1995) Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc. Natl. Acad. Sci. USA 92, 5734–5738.
Lyford G. L., Yamagata K., Kaufmann W. E., Barnes C. A., Sanders L. K., Copeland N. G., et al. (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14, 433–445.
Brakeman P. R., Lanahan A. A., O’Brien R., Roche K., Barnes C. A., Huganir R. L., et al. (1997) Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386, 284–288.
Morgan J. I., Cohen D. R., Hempstead J. L., and Curran T. (1987) Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237, 192–197.
Gass P., Herdegen T., Bravo R., and Kiessling M. (1992) Induction of immediate early gene encoded proteins in the rat hippocampus after bicuculline-induced seizures: differential expression of KROX-24, FOS and JUN proteins. Neuroscience 48, 315–324.
Xiao B., Tu J. C., Petralia R. S., Yuan J. P., Doan A., Breder C. D., et al. (1998) Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins. Neuron 21, 707–716.
Ginty D. D., Glowacka D., Bader D. S., Hidaka H., and Wagner J. A. (1991) Induction of immediate early genes by Ca2+ influx requires cAMP-dependent protein kinase in PC12 cells. J. Biol. Chem. 266, 17,454–17,458.
Rusanescu G., Qi H., Thomas S. M., Brugge J. S., and Halegoua S. (1995) Calcium influx induces neurite growth through a Src-Ras signaling cassette. Neuron 15, 1415–1425.
Sato M., Suzuki K., and Nakanishi S. (2001) NMDA receptor stimulation and brain-derived neurotrophic factor upregulate homer 1a mRNA via the mitogen-activated protein kinase cascade in cultured cerebellar granule cells. J. Neurosci. 21, 3797–3805.
Jones M. W., Errington M. L., French P. J., Fine A., Bliss T. V., Garel S., et al. (2001) A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat. Neurosci. 4, 289–296.
Plath N., Ohana O., Dammermann B., Waltereit R., Husi H., Blanquet V., et al. (2001) Aberrant LTP in arg3.1/arc knockout animals. Soc. Neurosci. Abstr. 27, 611.12.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Waltereit, R., Weller, M. Signaling from cAMP/PKA to MAPK and synaptic plasticity. Mol Neurobiol 27, 99–106 (2003). https://doi.org/10.1385/MN:27:1:99
Issue Date:
DOI: https://doi.org/10.1385/MN:27:1:99