Intracellular Calcium Waves Transmit Synaptic Information to the Nucleus in Hippocampal Pyramidal Neurons

  • Mark F. Yeckel
  • Amanda A. Sleeper
  • John S. Fitzpatrick
  • Daniel N. Hertle
  • Anna M. Hagenston
  • Robin T. Garner


Ca2+ waves provide a spatially and temporally unique intracellular signal that carries information from one region of the neuron to another. Despite the computational potential of such a mechanism, relatively little is known about the consequences of Ca2+ waves on neuronal function. In this chapter we review the basic properties of internal Ca2+ release and Ca2+ waves in hippocampal CA1 pyramidal neurons and how synaptically elicited Ca2+ waves influence the transcription factor CREB in an age-dependent manner.


Pyramidal Neuron CREB Binding Protein Hippocampal Pyramidal Neuron Endoplasmic Retic Inducible cAMP Early Repressor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Allbritton, N.L., Meyer, T., and Stryer, L. (1992) Range of messenger action of calcium ion and inositol 1,4,5-trisphosphate. Science 258, 1812–1815.PubMedCrossRefGoogle Scholar
  2. Bading, H. (2000) Transcription-dependent neuronal plasticity the nuclear calcium hypothesis. Eur. J. Biochem. 267, 5280–5283.PubMedCrossRefGoogle Scholar
  3. Bading, H., Segal, M.M., Sucher, N.J., Dudek, H., Lipton, S.A., and Greenberg, M.E. (1995) N-methyl-d-aspartate receptors are critical for mediating the effects of glutamate on intracellular calcium-concentration and immediate-early gene-expression in cultured hippocampal-neurons. Neuroscience 64, 653–664.PubMedCrossRefGoogle Scholar
  4. Bannister, N.J., and Larkman, A.U. (1995a) Dendritic morphology of CA1 pyramidal neurones from the rat hippocampus: I. Branching patterns. J. Comp. Neurol. 360, 150–160.CrossRefGoogle Scholar
  5. Bannister, N.J., and Larkman, A.U. (1995b) Dendritic morphology of CA1 pyramidal neurones from the rat hippocampus: Ii. Spine distributions. J. Comp. Neurol. 360, 161–171.Google Scholar
  6. Berridge, M.J. (1993) Inositol trisphosphate and calcium signalling. Nature 361, 315–325.PubMedCrossRefGoogle Scholar
  7. Berridge, M.J. (1998) Neuronal calcium signaling. Neuron 21, 13–26.PubMedCrossRefGoogle Scholar
  8. Bezprozvanny, I., Watras, J., and Ehrlich, B.E. (1991) Bell-shaped calcium-response curves of ins(1,4,5)p3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 351, 751–754.PubMedCrossRefGoogle Scholar
  9. Bito, H., Deisseroth, K., and Tsien, R.W. (1997) Ca2+-dependent regulation in neuronal gene expression. Curr. Opin. Neurobiol. 7, 419–429.PubMedCrossRefGoogle Scholar
  10. Bonni, A., Brunet, A., West, A.E., Datta, S.R., Takasu, M.A., and Greenberg, M.E. (1999) Cell survival promoted by the ras-mapk signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358–1362.PubMedCrossRefGoogle Scholar
  11. Callamaras, N., Marchant, J.S., Sun, X.P., and Parker, I. (1998) Activation and co-ordination of insp3-mediated elementary Ca2+ events during global Ca2+ signals in Xenopus oocytes. J. Physiol. 509 (Pt 1), 81–91.PubMedCrossRefGoogle Scholar
  12. Chen, Y., and Ghosh, A. (2005) Regulation of dendritic development by neuronal activity. J. Neurobiol. 64, 4–10.PubMedCrossRefGoogle Scholar
  13. Chrivia, J.C., Kwok, R.P., Lamb, N., Hagiwara, M., Montminy, M.R., and Goodman, R.H. (1993) Phosphorylated CREB binds specifically to the nuclear protein CPB. Nature 365, 855–859.PubMedCrossRefGoogle Scholar
  14. Costa, P.F. (1996) The kinetic parameters of sodium currents in maturing acutely isolated rat hippocampal CA1 neurones. Brain Res. Dev. Brain Res. 91, 29–40.PubMedCrossRefGoogle Scholar
  15. Dargan, S.L., Schwaller, B., and Parker, I. (2004) Spatiotemporal patterning of IP3-mediated Ca2+ signals in Xenopus oocytes by Ca2+-binding proteins. J. Physiol. 556, 447–461.PubMedCrossRefGoogle Scholar
  16. Dawson, A.P. (1997) Calcium signalling: How do IP3 receptors work? Curr. Biol. 7, R544–547.PubMedCrossRefGoogle Scholar
  17. Dawson, S.P., Keizer, J., and Pearson, J.E. (1999) Fire-diffuse-fire model of dynamics of intracellular calcium waves. Proc. Natl. Acad. Sci. USA 96, 6060–6063.PubMedCrossRefGoogle Scholar
  18. Deisseroth, K.H.E.K.T.R.W. (1998) Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature 392, 198–202.PubMedCrossRefGoogle Scholar
  19. Dijkhuizen, P.A., and Ghosh, A. (2005) BDNF regulates primary dendrite formation in cortical neurons via the PI3-kinase and map kinase signaling pathways. J. Neurobiol. 62, 278–288.PubMedCrossRefGoogle Scholar
  20. Dolmetsch, R.E., Pajvani, U., Fife, K., Spotts, J.M., and Greenberg, M.E. (2001) Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 294, 333–339.PubMedCrossRefGoogle Scholar
  21. Figurov, A., Pozzo-miller, L.D., Olafsson, P., Wang, T., and Lu, B. (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706–709.PubMedCrossRefGoogle Scholar
  22. Finch, E.A., and Augustine, G.J. (1998) Local calcium signalling by inositol-1,4,5-trisphosphate in purkinje cell dendrites. Nature 396, 753–756.PubMedCrossRefGoogle Scholar
  23. Finch, E.A., Turner, T.J., and Goldin, S.M. (1991) Calcium as a coagonist of inositol 1,4,5-trisphosphate-induced calcium release. Science 252, 443–446.PubMedCrossRefGoogle Scholar
  24. Gallin, W.J., and Greenberg, M.E. (1995) Calcium regulation of gene expression in neurons: The mode of entry matters. Curr. Opin. Neurobiol. 5, 367–374.PubMedCrossRefGoogle Scholar
  25. Ghosh, A., Carnahan, J., and Greenberg, M.E. (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263, 1618–1623.PubMedCrossRefGoogle Scholar
  26. Ghosh, A., and Greenberg, M.E. (1995) Calcium signaling in neurons - molecular mechanisms and cellular consequences. Science 268, 239–247.PubMedCrossRefGoogle Scholar
  27. Ginty, D.D. (1997) Calcium regulation of gene expression: Isn’t that spatial? Neuron 18, 183–186.PubMedCrossRefGoogle Scholar
  28. Hardingham, G.E., Arnold, F.J., and Bading, H. (2001) Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nat. Neurosci. 4, 261–267.PubMedCrossRefGoogle Scholar
  29. Hardingham, G.E., Cruzalegui, F.H., Chawla, S., and Bading, H. (1998) Mechanisms controlling gene expression by nuclear calcium signals. Cell Calcium 23, 131–134.PubMedCrossRefGoogle Scholar
  30. Iino, M. (1990) Biphasic Ca2+ dependence of inositol 1,4,5-trisphosphate-induced Ca2+ release in smooth muscle cells of the guinea pig taenia caeci. J. Gen. Physiol. 95, 1103–1122.PubMedCrossRefGoogle Scholar
  31. Jaffe, D.B., and Brown, T.H. (1994) Metabotropic glutamate-receptor activation induces calcium waves within hippocampal dendrites. J. Neurophys. 72, 471–474.Google Scholar
  32. Johenning, F.W., Zochowski, M., Conway, S.J., Holmes, A.B., Koulen, P., and Ehrlich, B.E. (2002) Distinct intracellular calcium transients in neurites and somata integrate neuronal signals. J. Neurosci. 22, 5344–5353.PubMedGoogle Scholar
  33. Jones, O.T., Bernstein, G.M., Jones, E.J., Jugloff, D.G., Law, M., Wong, W., and Mills, L.R. (1997) N-type calcium channels in the developing rat hippocampus: Subunit, complex, and regional expression. J. Neurosci. 17, 6152–6164.PubMedGoogle Scholar
  34. Kapur, A., Yeckel, M., and Johnston, D. (2001) Hippocampal mossy fiber activity evokes Ca2+ release in CA3 pyramidal neurons via a metabotropic glutamate receptor pathway. Neuroscience 107, 59–69.PubMedCrossRefGoogle Scholar
  35. Kasai, H., and Petersen, O.H. (1994) Spatial dynamics of second messengers: IP3 and cAMP as long-range and associative messengers. Trends Neurosci. 17, 95–101.PubMedCrossRefGoogle Scholar
  36. Koch, C., and Zador, A. (1993) The function of dendritic spines: Devices subserving biochemical rather than electrical compartmentalization. J. Neurosci. 13, 413–422.PubMedGoogle Scholar
  37. Kornhauser, J.M., Cowan, C.W., Shaywitz, A.J., Dolmetsch, R.E., Griffith, E.C., Hu, L.S., Haddad, C., Xia, Z., and Greenberg, M.E. (2002) CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events. Neuron 34, 221–233.PubMedCrossRefGoogle Scholar
  38. Kwok, R.P., Lundblad, J.R., Chrivia, J.C., Richards, J.P., Bachinger, H.P., Brennan, R.G., Roberts, S.G., Green, M.R., and Goodman, R.H. (1994) Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370, 223–226.PubMedCrossRefGoogle Scholar
  39. Larkum, M.E., Watanabe, S., Nakamura, T., Lasser-Ross, N., and Ross, W.N. (2003) Synaptically activated Ca2+ waves in layer 2/3 and layer 5 rat neocortical pyramidal neurons. J. Physiol. 549, 471–488.PubMedCrossRefGoogle Scholar
  40. Ledo, F., Kremer, L., Mellstrom, B., and Naranjo, J.R. (2002) Ca2+-dependent block of CREB-cbp transcription by repressor dream. EMBO J. 21, 4583–4592.PubMedCrossRefGoogle Scholar
  41. Leite, M.F., Burgstahler, A.D., and Nathanson, M.H. (2002) Ca2+ waves require sequential activation of inositol trisphosphate receptors and ryanodine receptors in pancreatic acini. Gastroenterology 122, 415–427.PubMedCrossRefGoogle Scholar
  42. Levitan, I.B. (1999) It is calmodulin after all! Mediator of the calcium modulation of multiple ion channels. Neuron 22, 645–648.PubMedCrossRefGoogle Scholar
  43. Marchant, J.S., and Taylor, C.W. (1997) Cooperative activation of IP3 receptors by sequential binding of IP3 and Ca2+ safeguards against spontaneous activity. Curr. Biol. 7, 510–518.PubMedCrossRefGoogle Scholar
  44. McAllister, A.K., Katz, L.C., and Lo, D.C. (1997) Opposing roles for endogenous bdnf and nt-3 in regulating cortical dendritic growth. Neuron 18, 767–778.PubMedCrossRefGoogle Scholar
  45. Mermelstein, P.G., Bito, H., Deisseroth, K., and Tsien, R.W. (2000) Critical dependence of camp response element-binding protein phosphorylation on L-type calcium channels supports a selective response to EPSPs in preference to action potentials. J. Neurosci. 20, 266–273.PubMedGoogle Scholar
  46. Messaoudi, E., Bardsen, K., Srebro, B., and Bramham, C.R. (1998) Acute intrahippocampal infusion of BDNF induces lasting potentiation of synaptic transmission in the rat dentate gyrus. J. Neurophys. 79, 496–499.Google Scholar
  47. Mioduszewska, B., Jaworski, J., and Kaczmarek, L. (2003) Inducible cAMP early repressor (icer) in the nervous system–a transcriptional regulator of neuronal plasticity and programmed cell death. J. Neurochem. 87, 1313–1320.PubMedCrossRefGoogle Scholar
  48. Moore, A.N., Waxham, M.N., and Dash, P.K. (1996) Neuronal activity increases the phosphorylation of the transcription factor camp response element-binding protein (CREB) in rat hippocampus and cortex. J. Biol. Chem. 271, 14214–14220.PubMedCrossRefGoogle Scholar
  49. Morikawa, H., Imani, F., Khodakhah, K., and Williams, J.T. (2000) Inositol 1,4,5-triphosphate-evoked responses in midbrain dopamine neurons. J. Neurosci. 20, RC103.PubMedGoogle Scholar
  50. Muller, W., and Conner, J.A. (1991) Dendritic spines as individual neuronal compartments for synaptic Ca2+ responses. Nature 354, 73–76.PubMedCrossRefGoogle Scholar
  51. Nakagawa, S., Kim, J.E., Lee, R., Chen, J., Fujioka, T., Malberg, J., Tsuji, S., and Duman, R.S. (2002) Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus. J. Neurosci. 22, 9868–9876.PubMedGoogle Scholar
  52. Nakamura, T., Barbara, J.G., Nakamura, K., and Ross, W.N. (1999) Synergistic release of Ca2+ from IP3-sensitive stores evoked by synaptic activation of mGluRs paired with backpropagating action potentials. Neuron 24, 727–737.PubMedCrossRefGoogle Scholar
  53. Nakamura, T., Lasser-Ross, N., Nakamura, K., and Ross, W.N. (2002) Spatial segregation and interaction of calcium signalling mechanisms in rat hippocampal CA1 pyramidal neurons. J. Physiol. 543, 465–480.PubMedCrossRefGoogle Scholar
  54. Nakamura, T., Nakamura, K., Lasser-Ross, N., Barbara, J.G., Sandler, V.M., and Ross, W.N. (2000) Inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release evoked by metabotropic agonists and backpropagating action potentials in hippocampal CA1 pyramidal neurons. J. Neurosci. 20, 8365–8376.PubMedGoogle Scholar
  55. Nguyen, P.V., Abel, T., and Kandel, E.R. (1994) Requirement of a critical period of transcription for induction of a late phase of LTP. Science 265, 1104–1107.PubMedCrossRefGoogle Scholar
  56. Patterson, S.L., Pittenger, C., Morozov, A., Martin, K.C., Scanlin, H., Drake, C., and Kandel, E.R. (2001) Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron 32, 123–140.PubMedCrossRefGoogle Scholar
  57. Petralia, R.S., Sans, N., Wang, Y.X., and Wenthold, R.J. (2005) Ontogeny of postsynaptic density proteins at glutamatergic synapses. Mol. Cell. Neurosci. 29, 436–452.PubMedCrossRefGoogle Scholar
  58. Power, J.M., and Sah, P. (2002) Nuclear calcium signaling evoked by cholinergic stimulation in hippocampal CA1 pyramidal neurons. J. Neurosci. 22, 3454–3462.PubMedGoogle Scholar
  59. Pozzo Miller, L.D., Petrozzino, J.J., Golarai, G., and Connor, J.A. (1996) Ca2+ release from intracellular stores induced by afferent stimulation of CA3 pyramidal neurons in hippocampal slices. J. Neurophys. 76, 554–562.Google Scholar
  60. Pyapali, G.K., Sik, A., Penttonen, M., Buzsaki, G., and Turner, D.A. (1998) Dendritic properties of hippocampal CA1 pyramidal neurons in the rat: Intracellular staining in vivo and in vitro. J. Comp. Neurol. 391, 335–352.PubMedCrossRefGoogle Scholar
  61. Redmond, L., and Ghosh, A. (2005) Regulation of dendritic development by calcium signaling. Cell Calcium 37, 411–416.PubMedCrossRefGoogle Scholar
  62. Redmond, L., Kashani, A.H., and Ghosh, A. (2002) Calcium regulation of dendritic growth via CAM kinase iv and CREB-mediated transcription. Neuron 34, 999–1010.PubMedCrossRefGoogle Scholar
  63. Riccio, A., Ahn, S., Davenport, C.M., Blendy, J.A., and Ginty, D.D. (1999) Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 286, 2358–2361.PubMedCrossRefGoogle Scholar
  64. Rivera, C., Voipio, J., Payne, J.A., Ruusuvuori, E., Lahtinen, H., Lamsa, K., Pirvola, U., Saarma, M., and Kaila, K. (1999) The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397, 251–255.PubMedCrossRefGoogle Scholar
  65. Sabatini, B.L., Maravall, M., and Svoboda, K. (2001) Ca2+ signaling in dendritic spines. Curr. Opin. Neurobiol. 11, 349–356.PubMedCrossRefGoogle Scholar
  66. Sala, C., Rudolph-Correia, S., and Sheng, M. (2000) Developmentally regulated nmda receptor-dependent dephosphorylation of camp response element-binding protein (CREB) in hippocampal neurons. J. Neurosci. 20, 3529–3536.PubMedGoogle Scholar
  67. Sanyal, S., Sandstrom, D.J., Hoeffer, C.A., and Ramaswami, M. (2002) Ap-1 functions upstream of CREB to control synaptic plasticity in drosophila. Nature 416, 870–874.PubMedCrossRefGoogle Scholar
  68. Sharp, A.H., McPherson, P.S., Dawson, T.M., Aoki, C., Campbell, K.P., and Snyder, S.H. (1993) Differential immunohistochemical localization of inositol 1,4,5- trisphosphate- and ryanodine-sensitive Ca2+ release channels in rat brain. J. Neurosci. 13, 3051–3063.PubMedGoogle Scholar
  69. Sharp, A.H., Nucifora, F.C., Jr., Blondel, O., Sheppard, C.A., Zhang, C., Snyder, S.H., Russell, J.T., Ryugo, D.K., and Ross, C.A. (1999) Differential cellular expression of isoforms of inositol 1,4,5-triphosphate receptors in neurons and glia in brain. J. Comp. Neurol. 406, 207–220.PubMedCrossRefGoogle Scholar
  70. Shaywitz, A.J., and Greenberg, M.E. (1999) CREB: A stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu. Rev. Biochem. 68, 821–861.PubMedCrossRefGoogle Scholar
  71. Sheng, M., Thompson, M.A., and Greenberg, M.E. (1991) CREB: A Ca2+-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252, 1427–1430.PubMedCrossRefGoogle Scholar
  72. Silva, A.J., Kogan, J.H., Frankland, P.W., and Kida, S. (1998) CREB and memory. Annu. Rev. Neurosci. 21, 127–148.PubMedCrossRefGoogle Scholar
  73. Svoboda, K., and Mainen, Z.F. (1999) Synaptic [Ca2+]: Intracellular stores spill their guts. Neuron 22, 427–430.PubMedCrossRefGoogle Scholar
  74. Turner, D.A., Buhl, E.H., Hailer, N.P., and Nitsch, R. (1998) Morphological features of the entorhinal-hippocampal connection. Prog. Neurobiol. 55, 537–562.PubMedCrossRefGoogle Scholar
  75. Verkhratsky, A., and Petersen, O.H. (2002) The endoplasmic reticulum as an integrating signalling organelle: From neuronal signalling to neuronal death. Eur. J. Pharmacol. 447, 141–154.PubMedCrossRefGoogle Scholar
  76. Watanabe, S., Hong, M., Lasser-Ross, N., and Ross, W.N. (2006) Modulation of calcium wave propagation in the dendrites and to the soma of rat hippocampal pyramidal neurons. J. Physiol. 575, 455–468.PubMedCrossRefGoogle Scholar
  77. Wells, D.G., and Fallon, J.R. (2000) Dendritic mRNA translation: Deciphering the uncoded. Nat. Neurosci. 3, 1062–1064.PubMedCrossRefGoogle Scholar
  78. West, A.E., Chen, W.G., Dalva, M.B., Dolmetsch, R.E., Kornhauser, J.M., Shaywitz, A.J., Takasu, M.A., Tao, X., and Greenberg, M.E. (2001) Calcium regulation of neuronal gene expression. Proc. Natl. Acad. Sci. USA 98, 11024–11031.PubMedCrossRefGoogle Scholar
  79. Wickens, J. (1988) Electrically coupled but chemically isolated synapses: Dendritic spines and calcium in a rule for synaptic modification. Prof. Neurobiol. 31, 507–528.CrossRefGoogle Scholar
  80. Wu, G.Y., Deisseroth, K., and Tsien, R.W. (2001) Activity-dependent CREB phosphorylation: Convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. USA 98, 2808–2813.PubMedCrossRefGoogle Scholar
  81. Yeckel, M.F., Kapur, A., and Johnston, D. (1999) Multiple forms of LTP in hippocampal CA3 neurons use a common postsynaptic mechanism. Nat. Neurosci. 2, 625–633.PubMedCrossRefGoogle Scholar
  82. Yuste, R., Majewska, A., and Holthoff, K. (2000) From form to function: Calcium compartmentalization in dendritic spines. Nat. Neurosci. 3, 653–659.PubMedCrossRefGoogle Scholar
  83. Zhou, S., and Ross, W.N. (2002) Threshold conditions for synaptically evoking Ca2+ waves in hippocampal pyramidal neurons. J. Neurophys. 87, 1799–1804.Google Scholar

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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Mark F. Yeckel
  • Amanda A. Sleeper
  • John S. Fitzpatrick
  • Daniel N. Hertle
  • Anna M. Hagenston
  • Robin T. Garner

There are no affiliations available

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