Abstract
Memory storage in mammalian neurons probably depends on both biochemical events and morphological alterations in dendrites. Here we report an activity-dependent stabilization of the MAP kinase (MAPK) pathway, prominent in hippocampal dendrites. The longevity of the signal in these dendrites was increased to hours when multiple spaced stimuli were used. Likewise, spaced stimuli and MAPK activation were critical for protrusion of new dendritic filopodia that also remained stable for hours. Our experiments define a new role for stimulus-specific responses of MAPK signaling in activity-dependent neuronal plasticity. The local biochemical signaling in dendrites complements MAPK signaling in gene expression. Together, these processes may support long-lasting behavioral changes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
206,07 € per year
only 17,17 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout







Similar content being viewed by others
References
Chang, F. L. & Greenough, W. T. Transient and enduring morphological correlates of synaptic activity and efficacy change in the rat hippocampal slice. Brain Res. 309, 35–46 (1984).
Maletic-Savatic, M., Malinow, R. & Svoboda, K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283, 1923–1927 (1999).
Engert, F. & Bonhoeffer, T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999).
Toni, N., Buchs, P. A., Nikonenko, I., Bron, C. R. & Muller, D. LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402, 421–425 (1999).
Hosokawa, T., Rusakov, D. A., Bliss, T. V. & Fine, A. Repeated confocal imaging of individual dendritic spines in the living hippocampal slice: evidence for changes in length and orientation associated with chemically induced LTP. J. Neurosci. 15, 5560–5573 (1995).
Martin, K. C. et al. MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. Neuron 18, 899–912 (1997).
Bailey, C. H. et al. Mutation in the phosphorylation sites of MAP kinase blocks learning-related internalization of apCAM in Aplysia sensory neurons. Neuron 18, 913–924 (1997).
Winder, D. G. et al. ERK plays a regulatory role in induction of LTP by theta frequency stimulation and its modulation by beta-adrenergic receptors. Neuron 24, 715–726 (1999).
English, J. D. & Sweatt, J.D. A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation. J. Biol. Chem. 272, 19103–19106 (1997).
Impey, S. et al. Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB- dependent transcription and ERK nuclear translocation. Neuron 21, 869–883 (1998).
Finkbeiner, S. et al. CREB: a major mediator of neuronal neurotrophin responses. Neuron 19, 1031–1047 (1997).
Hardingham, G. E., Chawla, S., Cruzalegui, F. H. & Bading, H. Control of recruitment and transcription-activating function of CBP determines gene regulation by NMDA receptors and L-type calcium channels. Neuron 22, 789–798 (1999).
Atkins, C. M., Selcher, J. C., Petraitis, J. J., Trzaskos, J. M. & Sweatt, J. D. The MAPK cascade is required for mammalian associative learning. Nat. Neurosci. 1, 602–609 (1998).
Blum, S., Moore, A. N., Adams, F. & Dash, P. K. 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 (1999).
Bading, H. & Greenberg, M. E. Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 253, 912–914 (1991).
Murphy, T. H. et al. Differential regulation of calcium/calmodulin-dependent protein kinase II and p42 MAP kinase activity by synaptic transmission. J. Neurosci. 14, 1320–1331 (1994).
Fields, R. D., Eshete, F., Stevens, B. & Itoh, K. Action potential-dependent regulation of gene expression: temporal specificity in ca2+, cAMP-responsive element binding proteins, and mitogen-activated protein kinase signaling. J. Neurosci. 17, 7252–7266 (1997).
Roberson, E. D. et al. 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 (1999).
Schafe, G. E., Nadel, N. V., Sullivan, G. M., Harris, A. & LeDoux, J. E. Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learn. Mem. 6, 97–110 (1999).
Yin, J. C. et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 79, 49–58 (1994).
Kogan, J. H. et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 7, 1–11 (1997).
Mauelshagen, J., Sherff, C. M. & Carew, T. J. Differential induction of long-term synaptic facilitation by spaced and massed applications of serotonin at sensory neuron synapses of Aplysia californica. Learn. Mem. 5, 246–256 (1998).
Michael, D. et al. Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons of Aplysia. Proc. Natl. Acad. Sci. USA 95, 1864–1869 (1998).
Deisseroth, K., Heist, E. K. & Tsien, R. W. Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392, 198–202 (1998).
Enslen, H., Tokumitsu, H., Stork, P. J., Davis, R. J. & Soderling, T. R. Regulation of mitogen-activated protein kinases by a calcium/calmodulin- dependent protein kinase cascade. Proc. Natl. Acad. Sci. USA 93, 10803–10808 (1996).
Chen, H. J., Rojas-Soto, M., Oguni, A. & Kennedy, M. B. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20, 895–904 (1998).
Rosen, L. B., Ginty, D. D., Weber, M. J. & Greenberg, M. E. Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras. Neuron 12, 1207–1221 (1994).
Brondello, J. M., Pouyssegur, J. & McKenzie, F. R. Reduced MAP kinase phosphatase-1 degradation after p42/p44(MAPK)-dependent phosphorylation. Science 286, 2514–2517 (1999).
Iyengar, R. Gating by cyclic AMP: expanded role for an old signaling pathway. Science 271, 461–463 (1996).
Vossler, M. R. et al. cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89, 73–82 (1997).
Seidel, M. G., Klinger, M., Freissmuth, M. & Holler, C. Activation of mitogen-activated protein kinase by the A(2A)-adenosine receptor via a rap1-dependent and via a p21(ras)-dependent pathway. J. Biol. Chem. 274, 25833–25841 (1999).
Favata, M. F. et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623–18632 (1998).
Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J. & Saltiel, A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl. Acad. Sci. USA 92, 7686–7689 (1995).
Edwards, F. A. Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation. Physiol. Rev. 75, 759–787 (1995).
McKinney, R. A., Capogna, M., Durr, R., Gahwiler, B. H. & Thompson, S.M. Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nat. Neurosci. 2, 44–49 (1999).
Fischer, M., Kaech, S., Wagner, U., Brinkhaus, H. & Matus, A. Glutamate receptors regulate actin-based plasticity in dendritic spines. Nat. Neurosci. 3, 887–894 (2000).
Dunaevsky, A., Tashiro, A., Majewska, A., Mason, C. & Yuste, R. Developmental regulation of spine motility in the mammalian central nervous system. Proc. Natl. Acad. Sci. USA 96, 13438–13443 (1999).
Sorra, K. E., Fiala, J. C. & Harris, K. M. Critical assessment of the involvement of perforations, spinules, and spine branching in hippocampal synapse formation. J. Comp. Neurol. 398, 225–240 (1998).
Ziv, N. E. & Smith, S. J. Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron 17, 91–102 (1996).
Brambilla, R. et al. A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390, 281–286 (1997).
Huang, Y. Y., Li, X. C. & Kandel, E. R. cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase. Cell 79, 69–79 (1994).
Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996).
Kavalali, E. T., Klingauf, J. & Tsien, R. W. Activity-dependent regulation of synaptic clustering in a hippocampal culture system. Proc. Natl. Acad. Sci. USA 96, 12893–12900 (1999).
Murphy, D. D. & Segal, M. Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein. Proc. Natl. Acad. Sci. USA 94, 1482–1487 (1997).
Casadio, A. et al. A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99, 221–237 (1999).
Bito, H., Deisseroth, K. & Tsien, R. W. CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87, 1203–1214 (1996).
Raught, B. & Gingras, A.C. eIF4E activity is regulated at multiple levels. Int. J. Biochem. Cell. Biol. 31, 43–57 (1999).
Schuman, E. M. mRNA trafficking and local protein synthesis at the synapse. Neuron 23, 645–648 (1999).
Frey, U. & Morris, R. G. Synaptic tagging and long-term potentiation. Nature 385, 533–536 (1997).
Wu, G. Y. & Cline, H. T. Stabilization of dendritic arbor structure in vivo by CaMKII. Science 279, 222–226 (1998).
Acknowledgements
We thank H. Cline and H. Reuter for reading the manuscript, and members of the Tsien lab for comments and discussion. We also thank Y.-Q. Cao for her help in the western blot experiments. This study was supported by the NIH.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wu, GY., Deisseroth, K. & Tsien, R. Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology. Nat Neurosci 4, 151–158 (2001). https://doi.org/10.1038/83976
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/83976