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Nuclear calcium signalling in the regulation of brain function

Nature Reviews Neuroscience volume 14, pages 593–608 (2013)Cite this article

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Key Points

  • Nuclear calcium is an important mediator of activity-dependent gene expression in the nervous system. It serves as a signalling end point in synapse-to-nucleus communication and activates gene programmes needed for the long-term implementation of many neuroadaptations, including memory consolidation, acquired neuroprotection and the development of chronic pain. The requirement of nuclear calcium signals for long-term memory formation is evolutionarily conserved from flies to mammals.

  • The mechanism through which synaptic activity leads to increases in the intranuclear calcium concentration involves stimulation of synaptic NMDA receptors, generation of backpropagating action potentials and the opening of voltage-gated calcium channels. Nuclear calcium transients may also be initiated or enhanced by calcium release from intracellular calcium stores mediated by inositol triphosphate or ryanodine receptors.

  • Nuclear calcium is one of the most potent regulators of gene expression. It controls the activity or nuclear localization of several transcriptional regulators (which include CREB (cyclic AMP-responsive element-binding protein), CBP (CREB-binding protein), class IIa HDACs (histone deactylases) and MECP2 (metyhyl-CpG-binding protein 2)) that either generate or interpret chromatin modifications.

  • The target gene pool of nuclear calcium signalling comprises nearly 200 genes that function, for example, in the regulation of dendrite architecture and spine density and shape. The neuroprotective activity of nuclear calcium signalling appears to be mediated by a set of genes that render mitochondria more resistant to harmful conditions.

  • The effects of nuclear calcium on gene regulation and neuroprotection are antagonized by the stimulation of extrasynaptic NMDA receptors that trigger transcriptional shut-off and cell death pathways.

  • Dysfunctioning of nuclear calcium signalling, referred to as 'nuclear calciopathy', may be a common factor in the aetiology of neurodegenerative and neuropsychiatric conditions. The modulation of nuclear calcium signalling may be a novel therapeutic strategy for the treatment of neurological disorders.

Abstract

Synaptic activity initiates biochemical processes that have various outcomes, including the formation of memories, increases in neuronal survival and the development of chronic pain and addiction. Virtually all activity-induced, long-lasting adaptations of brain functions require a dialogue between synapses and the nucleus that results in changes in gene expression. Calcium signals that are induced by synaptic activity and propagate into the nucleus are a major route for synapse-to-nucleus communication. Recent findings indicate that diverse forms of neuroadaptation require calcium transients in the nucleus to switch on the necessary genomic programme. Deficits in nuclear calcium signalling as a result of a reduction in synaptic activity or increased extrasynaptic NMDA receptor signalling may underlie the aetiologies of various diseases, including neurodegeneration and cognitive dysfunction.

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Figure 1: Detection of nuclear calcium signals in models of neuronal plasticity, learning and memory, and pain.
Figure 2: Mechanisms by which synaptic activity can generate nuclear calcium transients.
Figure 3: Transcriptional regulation by nuclear calcium signals.
Figure 4: Nuclear calcium-regulated transcriptional regulators control diverse forms of neuroadaptation.
Figure 5: 'Nuclear calciopathy' as a common factor in the aetiology of neurodegenerative and cognitive disorders.

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References

  1. Berridge, M. J., Lipp, P. & Bootman, M. D. The versatility and universality of calcium signalling. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000).

    CAS  Google Scholar 

  2. Hagenston, A. M. & Bading, H. Calcium signaling in synapse-to-nucleus communication. Cold Spring Harb. Perspect. Biol. 3, a004564 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. Zhang, S. J. et al. Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity. PLoS Genet. 5, e1000604 (2009). This study identified nuclear calcium as one of the most potent regulators of neuronal gene expression and uncovered a large pool of 185 nuclear calcium-regulated genes.

    PubMed  PubMed Central  Google Scholar 

  4. Hardingham, G. E. & Bading, H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nature Rev. Neurosci. 11, 682–696 (2010).

    CAS  Google Scholar 

  5. Bliss, T. V. & Collingridge, G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006).

    CAS  PubMed  Google Scholar 

  7. Lynch, M. A. Long-term potentiation and memory. Physiol. Rev. 84, 87–136 (2004).

    CAS  PubMed  Google Scholar 

  8. Kauer, J. A. & Malenka, R. C. Synaptic plasticity and addiction. Nature Rev. Neurosci. 8, 844–858 (2007).

    CAS  Google Scholar 

  9. Bading, H. Transcription-dependent neuronal plasticity: the nuclear calcium hypothesis. Eur. J. Biochem. 267, 5280–5283 (2000). This paper was the first to suggest that nuclear calcium functions as a common regulator of different forms of transcription-dependent adaptations in the nervous system.

    CAS  PubMed  Google Scholar 

  10. Greer, P. L. & Greenberg, M. E. From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 59, 846–860 (2008).

    CAS  PubMed  Google Scholar 

  11. Ch'ng, T. H. & Martin, K. C. Synapse-to-nucleus signaling. Curr. Opin. Neurobiol. 21, 345–352 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Milner, B., Squire, L. R. & Kandel, E. R. Cognitive neuroscience and the study of memory. Neuron 20, 445–468 (1998).

    CAS  PubMed  Google Scholar 

  13. Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001).

    CAS  PubMed  Google Scholar 

  14. Montarolo, P. G. et al. A critical period for macromolecular synthesis in long-term heterosynaptic facilitation in Aplysia. Science 234, 1249–1254 (1986). This is a landmark paper that provided evidence for the requirement of RNA and protein synthesis for long-lasting synaptic and behavioural plasticity.

    CAS  PubMed  Google Scholar 

  15. Davis, R. L. Traces of Drosophila memory. Neuron 70, 8–19 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Keene, A. C. & Waddell, S. Drosophila olfactory memory: single genes to complex neural circuits. Nature Rev. Neurosci. 8, 341–354 (2007).

    CAS  Google Scholar 

  17. Silva, A. J. Molecular and cellular cognitive studies of the role of synaptic plasticity in memory. J. Neurobiol. 54, 224–237 (2003).

    CAS  PubMed  Google Scholar 

  18. Nguyen, P. V., Abel, T. & Kandel, E. R. Requirement of a critical period of transcription for induction of a late phase of LTP. Science 265, 1104–1107 (1994). This study identified the transcription dependency of late-phase long-term potentiation in the rat hippocampus. The close parallels with the transcription dependency of long-term facilitation in A. californica (reference 14) revealed a commonality between mammals and invertebrates, suggesting the possibility of similar molecular pathways underlying transcription-dependent plasticity.

    CAS  PubMed  Google Scholar 

  19. Ahn, S., Ginty, D. D. & Linden, D. J. A late phase of cerebellar long-term depression requires activation of CaMKIV and CREB. Neuron 23, 559–568 (1999).

    CAS  PubMed  Google Scholar 

  20. Ji, R. R., Kohno, T., Moore, K. A. & Woolf, C. J. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 26, 696–705 (2003).

    CAS  PubMed  Google Scholar 

  21. Nestler, E. J. Molecular basis of long-term plasticity underlying addiction. Nature Rev. Neurosci. 2, 119–128 (2001).

    CAS  Google Scholar 

  22. Woolf, C. J. & Costigan, M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc. Natl Acad. Sci. USA 96, 7723–7730 (1999).

    CAS  PubMed  Google Scholar 

  23. Mao, Z., Bonni, A., Xia, F., Nadal-Vicens, M. & Greenberg, M. E. Neuronal activity-dependent cell survival mediated by transcription factor MEF2. Science 286, 785–790 (1999).

    CAS  PubMed  Google Scholar 

  24. Hardingham, G. E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and death pathways. Nature Neurosci. 5, 405–415 (2002). This study uncovered the antagonistic functions of synaptic and extrasynaptic NMDARs in the regulation of CREB-mediated transcription and cell survival and/or death pathways.

    CAS  PubMed  Google Scholar 

  25. Zhang, S.-J. et al. Decoding NMDA receptor signaling: identification of genomic programs specifying neuronal survival and death. Neuron 53, 549–562 (2007).

    CAS  PubMed  Google Scholar 

  26. Rusak, B., Robertson, H. A., Wisden, W. & Hunt, S. P. Light pulses that shift rhythms induce gene expression in the suprachiasmatic nucleus. Science 248, 1237–1240 (1990).

    CAS  PubMed  Google Scholar 

  27. Ginty, D. D. et al. Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science 260, 238–241 (1993).

    CAS  PubMed  Google Scholar 

  28. Caroni, P. Neuro-regeneration: plasticity for repair and adaptation. Essays Biochem. 33, 53–64 (1998).

    CAS  PubMed  Google Scholar 

  29. Rossi, F., Gianola, S. & Corvetti, L. Regulation of intrinsic neuronal properties for axon growth and regeneration. Prog. Neurobiol. 81, 1–28 (2007).

    CAS  PubMed  Google Scholar 

  30. Deisseroth, K. et al. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42, 535–552 (2004).

    CAS  PubMed  Google Scholar 

  31. Carafoli, E. & Penniston, J. T. The calcium signal. Sci. Am. 253, 70–78 (1985).

    CAS  PubMed  Google Scholar 

  32. Clapham, D. E. Calcium signaling. Cell 131, 1047–1058 (2007).

    CAS  PubMed  Google Scholar 

  33. Berridge, M. J. Neuronal calcium signaling. Neuron 21, 13–26 (1998). A classical review that particularly highlights the role of the ER as a 'neuron-within-a-neuron' in the regulation of excitability, neurotransmitter release, synaptic plasticity and gene expression by neuronal calcium signals.

    CAS  PubMed  Google Scholar 

  34. Pizzo, P., Lissandron, V., Capitanio, P. & Pozzan, T. Calcium signalling in the Golgi apparatus. Cell Calcium 50, 184–192 (2011).

    CAS  PubMed  Google Scholar 

  35. Berridge, M. J. & Irvine, R. F. Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312, 315–321 (1984).

    CAS  PubMed  Google Scholar 

  36. Poser, S. & Storm, D. R. Role of Ca2+-stimulated adenylyl cyclases in LTP and memory formation. Int. J. Dev. Neurosci. 19, 387–394 (2001).

    CAS  PubMed  Google Scholar 

  37. Kiss, J. P. & Vizi, E. S. Nitric oxide: a novel link between synaptic and nonsynaptic transmission. Trends Neurosci. 24, 211–215 (2001).

    CAS  PubMed  Google Scholar 

  38. Ferguson, G. D. & Storm, D. R. Why calcium-stimulated adenylyl cyclases? Physiology (Bethesda) 19, 271–276 (2004).

    CAS  Google Scholar 

  39. Steinert, J. R., Chernova, T. & Forsythe, I. D. Nitric oxide signaling in brain function, dysfunction, and dementia. Neuroscientist 16, 435–452 (2010).

    CAS  PubMed  Google Scholar 

  40. Bading, H. & Greenberg, M. E. Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 253, 912–914 (1991).

    CAS  PubMed  Google Scholar 

  41. 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).

    CAS  PubMed  Google Scholar 

  42. Farnsworth, C. L. et al. Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF. Nature 376, 524–527 (1995).

    CAS  PubMed  Google Scholar 

  43. 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).

    CAS  PubMed  Google Scholar 

  44. Wiegert, J. S., Bengtson, C. P. & Bading, H. Diffusion and not active transport underlies and limits ERK1/2 synapse-to-nucleus signaling in hippocampal neurons. J. Biol. Chem. 282, 29621–29633 (2007).

    CAS  PubMed  Google Scholar 

  45. Nakazawa, H. & Murphy, T. H. Activation of nuclear calcium dynamics by synaptic stimulation in cultured cortical neurons. J. Neurochem. 73, 1075–1083 (1999).

    CAS  PubMed  Google Scholar 

  46. Power, J. M. & Sah, P. Nuclear calcium signaling evoked by cholinergic stimulation in hippocampal CA1 pyramidal neurons. J. Neurosci. 22, 3454–3462 (2002).

    CAS  PubMed  Google Scholar 

  47. Power, J. M. & Sah, P. Distribution of IP3-mediated calcium responses and their role in nuclear signalling in rat basolateral amygdala neurons. J. Physiol. 580, 835–857 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Watanabe, S., Hong, M., Lasser-Ross, N. & Ross, W. N. Modulation of calcium wave propagation in the dendrites and to the soma of rat hippocampal pyramidal neurons. J. Physiol. 575, 455–468 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Hagenston, A. M., Fitzpatrick, J. S. & Yeckel, M. F. MGluR-mediated calcium waves that invade the soma regulate firing in layer V medial prefrontal cortical pyramidal neurons. Cereb. Cortex 18, 407–423 (2008).

    PubMed  Google Scholar 

  50. Bengtson, C. P., Freitag, H. E., Weislogel, J.-M. & Bading, H. Nuclear calcium sensors reveal that repetition of trains of synaptic stimuli boosts nuclear calcium signaling in CA1 pyramidal neurons. Biophys. J. 99, 4066–4077 (2010). This study, in which a nuclear localized recombinant calcium sensor was used for the first time in neurons, revealed that late-phase long-term potentiation-inducing synaptic stimulations evoke robust nuclear calcium responses. It uncovered a strong interdependency between spike generation and the nuclear calcium signal, both of which dramatically increase with burst repetition. Nuclear calcium signals were sensitive to blockers of L-type calcium channels and NMDARs but not sensitive to a metabotropic glutamate receptor antagonist or internal calcium store depletion.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. O'Malley, D. M. Calcium permeability of the neuronal nuclear envelope: evaluation using confocal volumes and intracellular perfusion. J. Neurosci. 14, 5741–5758 (1994).

    CAS  PubMed  Google Scholar 

  52. Eder, A. & Bading, H. Calcium signals can freely cross the nuclear envelope in hippocampal neurons: somatic calcium increases generate nuclear calcium transients. BMC Neurosci. 8, 57 (2007).

    PubMed  PubMed Central  Google Scholar 

  53. Simonetti, M. et al. Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain. Neuron 77, 43–57 (2013). This study was the first to show that nuclear calcium also controls a pathological adaptive process in the nervous system. Nuclear calcium transients induced in spinal cords neurons by the exposure of mice to a noxious stimulus were identified as key signals in the activation of a gene programme that is required for the transition of acute nociceptive sensitization to persistent inflammatory pain.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Weislogel, J.-M. et al. Requirement of nuclear calcium signaling in Drosophila long-term memory. Sci. Signal. 6, ra33 (2013). This study provided the first evidence for a learning-associated nuclear calcium signal in vivo and identified nuclear calcium as an evolutionary conserved signal required for long-term memory formation.

    PubMed  Google Scholar 

  55. Stuart, G. J. & Sakmann, B. Active propagation of somatic action potentials into neocortical pyramidal cell dendrites. Nature 367, 69–72 (1994).

    CAS  PubMed  Google Scholar 

  56. Ahlijanian, M. K., Westenbroek, R. E. & Catterall, W. A. Subunit structure and localization of dihydropyridine-sensitive calcium channels in mammalian brain, spinal cord, and retina. Neuron 4, 819–832 (1990).

    CAS  PubMed  Google Scholar 

  57. Westenbroek, R. E., Ahlijanian, M. K. & Catterall, W. A. Clustering of L-type Ca2+ channels at the base of major dendrites in hippocampal pyramidal neurons. Nature 347, 281–284 (1990).

    CAS  PubMed  Google Scholar 

  58. Greenberg, M. E., Ziff, E. B. & Green, L. A. Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science 234, 80–83 (1986).

    CAS  PubMed  Google Scholar 

  59. Morgan, J. I. & Curran, T. Role of ion flux in the control of c-fos expression. Nature 322, 552–555 (1986). References 58 and 59 describe that opening of L-type calcium channels after membrane depolarization of the mouse pheochromocytoma cell line PC12 triggers transcriptional induction of the c-Fos gene. These studies provided the first experimental evidence that electrical activity can cause changes in gene transcription, which led to the concept of activity-dependent gene regulation in neurons.

    CAS  PubMed  Google Scholar 

  60. Murphy, T. H., Worley, P. F. & Baraban, J. M. L-type voltage-sensitive calcium channel mediate synaptic actvation of immediate early genes. Neuron 7, 625–635 (1991).

    CAS  PubMed  Google Scholar 

  61. Bading, H., Ginty, D. D. & Greenberg, M. E. Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways. Science 260, 181–186 (1993). This study identified calcium as the principal second messenger in the control of neuronal activity-dependent gene expression in hippocampal neurons and defined two distinct signalling pathways that couple calcium entry into neurons to the activation of transcription.

    CAS  PubMed  Google Scholar 

  62. Garaschuk, O., Yaari, Y. & Konnerth, A. Release and sequestration of calcium by ryanodine-sensitive stores in rat hippocampal neurons. J. Physiol. 502, 13–30 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Johenning, F. W. & Holthoff, K. Nuclear calcium signals during L-LTP induction do not predict the degree of synaptic potentiation. Cell Calcium 41, 271–283 (2007).

    CAS  PubMed  Google Scholar 

  64. Jaffe, D. B. & Brown, T. H. Metabotropic glutamate receptor activation induces calcium waves within hippocampal dendrites. J. Neurophysiol. 72, 471–474 (1994). The authors were the first to report calcium waves in hippocampal dendrites that were triggered by a focally applied metabotropic glutamate receptor agonist, suggesting a role for IP3 receptor-mediated calcium release in wave initiation and propagation.

    CAS  PubMed  Google Scholar 

  65. Markram, H., Helm, P. J. & Sakmann, B. Dendritic calcium transients evoked by single back-propagating action-potentials in rat neocortical pyramidal neurons. J. Physiol. 485, 1–20 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Power, J. M. & Sah, P. Intracellular calcium store filling by an L-type calcium current in the basolateral amygdala at subthreshold membrane potentials. J. Physiol. 562, 439–453 (2005).

    CAS  PubMed  Google Scholar 

  67. Hong, M. & Ross, W. N. Priming of intracellular calcium stores in rat CA1 pyramidal neurons. J. Physiol. 584, 75–87 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Bezprozvanny, I., Watras, J. & Ehrlich, B. E. Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 351, 751–754 (1991).

    CAS  PubMed  Google Scholar 

  69. Nakamura, T., Barbara, J. G., Nakamura, K. & Ross, W. N. Synergistic release of Ca2+ from IP3-sensitive stores evoked by synaptic activation of mGluRs paired with backpropagating action potentials. Neuron 24, 727–737 (1999). This was the first demonstration of synaptic activity-induced calcium waves in hippocampal pyramidal neurons that propagate through the proximal apical dendrite into the soma. The study identified an interplay between IP3 signals activated by metabotropic glutamate receptors and calcium entry through voltage-gated calcium channels activated by backpropagating action potentials.

    CAS  PubMed  Google Scholar 

  70. Nakamura, T., Lasser-Ross, N., Nakamura, K. & Ross, W. N. Spatial segregation and interaction of calcium signalling mechanisms in rat hippocampal CA1 pyramidal neurons. J. Physiol. 543, 465–480 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kapur, A., Yeckel, M. & Johnston, D. Hippocampal mossy fiber activity evokes Ca2+ release in CA3 pyramidal neurons via a metabotropic glutamate receptor pathway. Neuroscience 107, 59–69 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Larkum, M. E., Watanabe, S., Nakamura, T., Lasser-Ross, N. & Ross, W. N. Synaptically activated Ca2+ waves in layer 2/3 and layer 5 rat neocortical pyramidal neurons. J. Physiol. 549, 471–488 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Morikawa, H., Khodakhah, K. & Williams, J. T. Two intracellular pathways mediate metabotropic glutamate receptor-induced Ca2+ mobilization in dopamine neurons. J. Neurosci. 23, 149–157 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Shemer, I., Brinne, B., Tegner, J. & Grillner, S. Electrotonic signals along intracellular membranes may interconnect dendritic spines and nucleus. PLoS Comput. Biol. 4, e1000036 (2008).

    PubMed  PubMed Central  Google Scholar 

  75. Mazzanti, M., Bustamante, J. O. & Oberleithner, H. Electrical dimension of the nuclear envelope. Physiol. Rev. 81, 1–19 (2001).

    CAS  PubMed  Google Scholar 

  76. Matzke, A. J., Weiger, T. M. & Matzke, M. Ion channels at the nucleus: electrophysiology meets the genome. Mol. Plant 3, 642–652 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Hardingham, G. E., Chawla, S., Johnson, C. M. & Bading, H. Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385, 260–265 (1997). This study provided the first evidence for a role of nuclear calcium in gene regulation and identified CREB as a nuclear calcium-regulated transcription factor.

    CAS  PubMed  Google Scholar 

  78. Brini, M. et al. Nuclear Ca2+ concentration measured with specifically targeted recombinant aequorin. EMBO J. 12, 4813–4819 (1993). This study was the first to use a protein-based, nuclear-targeted calcium sensor.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Williams, D. A., Fogarty, K. E., Tsien, R. Y. & Fay, F. S. Calcium gradients in single smooth muscle cells revealed by the digital imaging microscope using Fura-2. Nature 318, 558–561 (1985). Using Fura-2 calcium imaging of smooth muscle cells, the authors were the first to report that increases in the intracellular calcium concentration can invade the cell nucleus.

    CAS  PubMed  Google Scholar 

  80. Hill, C. S. & Treisman, R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 80, 199–211 (1995).

    CAS  PubMed  Google Scholar 

  81. Knöll, B. & Nordheim, A. Functional versatility of transcription factors in the nervous system: the SRF paradigm. Trends Neurosci. 32, 432–442 (2009).

    PubMed  Google Scholar 

  82. Hardingham, G. E., Arnold, F. J. L. & Bading, H. A calcium microdomain near NMDA receptors: on-switch for ERK-dependent synapse-to-nucleus communication. Nature Neurosci. 4, 565–566 (2001).

    CAS  PubMed  Google Scholar 

  83. Christy, B. & Nathans, D. Functional serum response elements upstream of the growth factor-inducible gene zif268. Mol. Cell. Biol. 9, 4889–4895 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Janssen-Timmen, U., Lemaire, P., Mattei, M. G., Revelant, O. & Charnay, P. Structure, chromosome mapping and regulation of the mouse zinc-finger gene Krox-24; evidence for a common regulatory pathway for immediate-early serum-response genes. Gene 80, 325–336 (1989).

    CAS  PubMed  Google Scholar 

  85. Thiel, G., Mayer, S. I., Müller, I., Stefano, L. & Rössler, O. G. Egr-1–A Ca2+-regulated transcription factor. Cell Calcium 47, 397–403 (2010).

    CAS  PubMed  Google Scholar 

  86. Hardingham, G. E., Arnold, F. J. L. & Bading, H. Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity. Nature Neurosci. 4, 261–267 (2001).

    CAS  PubMed  Google Scholar 

  87. Chawla, S., Hardingham, G. E., Quinn, D. R. & Bading, H. CBP: a signal-regulated transcriptional coactivator controlled by nuclear calcium and CaM kinase IV. Science 281, 1505–1509 (1998). This study showed that CBP, a co-activator that interacts with CREB and numerous other transcription factors, is a target of nuclear calcium–CaMKIV signalling. Through recruitment of CBP, nuclear calcium inducibility may be conferred to many transcription factors, providing a mechanism for the regulation of a large number of genes.

    CAS  PubMed  Google Scholar 

  88. 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).

    CAS  PubMed  Google Scholar 

  89. Goldman, P. S., Tran, V. K. & Goodman, R. H. The multifunctional role of the co-activator CBP in transcriptional regulation. Recent Prog. Horm. Res. 52, 103–119 (1997).

    CAS  PubMed  Google Scholar 

  90. Cruzalegui, F. H., Hardingham, G. E. & Bading, H. c-Jun functions as a calcium-regulated transcriptional activator in the absence of JNK/SAPK1 activation. EMBO J. 18, 1335–1344 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Jensen, K. F., Ohmstede, C. A., Fisher, R. S. & Sahyoun, N. Nuclear and axonal localization of Ca2+/calmodulin-dependent protein kinase type Gr in rat cerebellar cortex. Proc. Natl Acad. Sci. USA 88, 2850–2853 (1991).

    CAS  PubMed  Google Scholar 

  92. Sorderling, T. R. The Ca-calmodulin-dependent protein kinase cascade. Trends Biochem. Sci. 24, 232–236 (1999).

    Google Scholar 

  93. Chow, F. A., Anderson, K. A., Noeldner, P. K. & Means, A. R. The autonomous activity of calcium/calmodulin-dependent protein kinase IV is required for its role in transcription. J. Biol. Chem. 280, 20530–20538 (2005).

    CAS  PubMed  Google Scholar 

  94. Montminy, M. Transcriptional regulation by cyclic AMP. Annu. Rev. Biochem. 66, 807–822 (1997).

    CAS  PubMed  Google Scholar 

  95. Mayr, B. & Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nature Rev. Mol. Cell Biol. 2, 599–609 (2001).

    CAS  Google Scholar 

  96. Zhang, X. et al. Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc. Natl Acad. Sci. USA 102, 4459–4464 (2005).

    CAS  PubMed  Google Scholar 

  97. Impey, S. et al. Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV. Neuron 34, 235–244 (2000).

    Google Scholar 

  98. Orphanides, G. & Reinberg, D. RNA polymerase II elongation through chromatin. Nature. 407, 471–475 (2000).

    CAS  PubMed  Google Scholar 

  99. Vo, N. & Goodman, R. H. CREB-binding protein and p300 in transcriptional regulation. J. Biol. Chem. 276, 13505–13508 (2001).

    CAS  PubMed  Google Scholar 

  100. Chawla, S., Vanhoutte, P., Arnold, F. J. L., Huang, C. L.-H. & Bading, H. Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J. Neurochem. 85, 151–159 (2003).

    CAS  PubMed  Google Scholar 

  101. Sando, R. et al. HDAC4 governs a transcriptional program essential for synaptic plasticity and memory. Cell 151, 821–834 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Schlumm, F., Mauceri, D. Freitag, H. E. & Bading, H. Nuclear calcium signaling regulates nuclear export of a subset of class IIa histone deacetylases following synaptic activity. J. Biol. Chem. 288, 8074–8084 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Martinovich, K. et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302, 890–893 (2003).

    Google Scholar 

  104. Chen, W. G. et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003).

    CAS  PubMed  Google Scholar 

  105. Lubin, F. D., Roth, T. L. & Sweatt, J. D. Epigenetic regulation of bdnf gene transcription in the consolidation of fear memory. J. Neurosci. 28, 10576–10586 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Guo, J. U. et al. Neuronal activity modifies the DNA methylation landscape in the adult brain. Nature Neurosci. 14, 1345–1351 (2011).

    CAS  PubMed  Google Scholar 

  107. Baker-Andresen, D., Ratnu, V. S. & Bredy, T. W. Dynamic DNA methylation: a prime candidate for genomic metaplasticity and behavioral adaption. Trends Neurosci. 36, 3–13 (2013).

    CAS  PubMed  Google Scholar 

  108. Moore, L. D., Le, T. & Fan, G. DNA methylation and its basic function. Neuropsychopharmacology 38, 23–38 (2013).

    CAS  PubMed  Google Scholar 

  109. Bird, A. P. & Wolffe, A. P. Methylation-induced repression-belsts, braces, and chromatin. Cell 99, 451–454 (1999).

    CAS  PubMed  Google Scholar 

  110. Hermann, A., Gowher, H. & Jeltsch, A. Biochemistry and biology of mammalian DNA methyltransferases. Cell. Mol. Life Sci. 61, 2571–2587 (2004).

    CAS  PubMed  Google Scholar 

  111. Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Suzuki, M. M. & Bird, A. DNA methylation landscapes: provocative insights from epigenomics. Nature Rev. Genet. 9, 465–476 (2008).

    CAS  PubMed  Google Scholar 

  113. Oliveira, A. M., Hemstedt, T. J. & Bading, H. Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities. Nature Neurosci. 15, 1111–1113 (2012).

    CAS  PubMed  Google Scholar 

  114. Chen, T., Ueda, Y., Xie, S. & Li, E. A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation. J. Biol. Chem. 277, 38746–38754 (2002).

    CAS  PubMed  Google Scholar 

  115. Guy, J., Cheval, H., Selfridge, J. & Bird, A. The role of MeCP2 in the brain. Annu. Rev. Cell Dev. Biol. 27, 631–652 (2011).

    CAS  PubMed  Google Scholar 

  116. West, A. E. & Greenberg, M. E. Neuronal activity-regulated gene transcription in synapse development and cognitive function. Cold Spring Harb. Perspect. Biol. 3, a005744 (2011).

    PubMed  PubMed Central  Google Scholar 

  117. Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007).

    CAS  PubMed  Google Scholar 

  118. Zhou, Z. et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255–269 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Skene, P. J. et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Cohen, S. et al. Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72, 72–85 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Tao, J. et al. Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function. Proc. Natl Acad. Sci. USA 106, 4882–4887 (2009).

    CAS  PubMed  Google Scholar 

  122. Gonzales, M. L., Adams, S., Dunaway, K. W. & LaSalle, J. M. Phosphorylation of distinct sites in MeCP2 modifies cofactor associations and the dynamics of transcriptional regulation. Mol. Cell. Biol. 32, 2894–2903 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Buchthal, B., Lau, D., Weiss, U., Weislogel, J.-M. & Bading, H. Nuclear calcium signaling controls methyl-CpG-binding protein 2 (MeCP2) phosphorylation on serine 421 following synaptic activity. J. Biol. Chem. 287, 30967–30974 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Carrion, A. M., Link, W. A., Ledo, F., Mellstrom, B. & Naranjo, J. R. DREAM is a Ca2+-regulated transcriptional repressor. Nature 398, 80–84 (1999).

    CAS  PubMed  Google Scholar 

  125. Osawa, M. et al. Calcium-regulated DNA binding and oligomerization of the neuronal calcium-sensing protein, calsenilin/DREAM/KChIP3 . J. Biol. Chem. 276, 41005–41013 (2001).

    CAS  PubMed  Google Scholar 

  126. Mellström, B. & Naranjo, J. R. Ca2+-dependent transcriptional repression and derepression: DREAM, a direct effector. Semin. Cell Dev. Biol. 12, 59–63 (2001).

    PubMed  Google Scholar 

  127. Ledo, F. et al. The DREAM–DRE interaction: key nucleotides and dominant negative mutants. Biochim. Biophys. Acta 1498, 162–168 (2000).

    CAS  PubMed  Google Scholar 

  128. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857–868 (1999).

    CAS  PubMed  Google Scholar 

  129. Burgering, B. M. & Kops, G. J. Cell cycle and death control: long live Forkheads. Trends Biochem. Sci. 27, 352–360 (2002).

    CAS  PubMed  Google Scholar 

  130. Dick, O. & Bading, H. Synaptic activity and nuclear calcium signaling protects hippocampal neurons from death signal-associated nuclear translocation of FoxO3a induced by extrasynaptic NMDA receptors. J. Biol. Chem. 285, 19354–19361 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Limback-Stokin, K., Korzus, E., Nagaoka-Yasuda, R. & Mayford, M. Nuclear calcium/calmodulin regulates memory consolidation. J. Neurosci. 24, 10858–10867 (2004). Using transgenic mice that express an inhibitor of nuclear calcium/calmodulin signalling in the forebrain, the authors provided the first evidence for a role of nuclear calcium signalling in the formation of long-term memory.

    PubMed  PubMed Central  Google Scholar 

  132. Papadia, S., Stevenson, P., Hardingham, N. R., Bading, H. & Hardingham, G. E. Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection. J. Neurosci. 25, 4279–4287 (2005). This paper was the first to show a role for nuclear calcium signalling in acquired neuroprotection.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Lau, D. & Bading, H. Synaptic activity-mediated suppression of p53 and induction of nuclear calcium-regulated neuroprotective genes promote survival through inhibition of mitochondrial permeability transition. J. Neurosci. 29, 4420–4429 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Mauceri, D., Freitag, H. E., Oliveira, A. M., Bengtson, C. P. & Bading, H. Nuclear calcium-VEGFD signaling controls maintenance of dendrite arborization necessary for memory formation. Neuron 71, 117–130 (2011). This study established a role for nuclear calcium signalling in the regulation of dendrite geometry and spine density. It identified VEGFD as a target gene of nuclear calcium signalling that is required both for the maintenance of a complex dendrite arbor and for cognitive functions.

    CAS  PubMed  Google Scholar 

  135. Wang, J. et al. Functional elimination of calmodulin within the nucleus by targeted expression of an inhibitor peptide. J. Biol. Chem. 270, 30245–30248 (1995).

    CAS  PubMed  Google Scholar 

  136. Zhang, S. J. et al. A signaling cascade of nuclear calcium–CREB-ATF3 activated by synaptic NMDA receptors defines a gene repression module that protects against extrasynaptic NMDA receptor-induced neuronal cell death and ischemic brain damage. J. Neurosci. 31, 4978–4990 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Bas-Orth, C. & Bading, H. The divergence-convergence model of acquired neuroprotection. Mech. Dev. 130, 396–401 (2013).

    CAS  PubMed  Google Scholar 

  138. Kang, H. et al. An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory. Cell 106, 771–783 (2001). This study established a role for CaMKIV, a key target of nuclear calcium signalling, in the formation of hippocampus-dependent long-term memory in mice.

    CAS  PubMed  Google Scholar 

  139. Marie, H., Morishita, W., Yu, X., Calakos, N. & Malenka, R. C. Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron. 45, 741–752 (2005).

    CAS  PubMed  Google Scholar 

  140. Plath, N. et al. Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52, 437–444 (2006).

    CAS  PubMed  Google Scholar 

  141. Jaubert, P. J. et al. Complex, multimodal behavioral profile of the Homer1 knockout mouse. Genes Brain Behav. 6, 141–154 (2007).

    CAS  PubMed  Google Scholar 

  142. Ploski, J. E., Monsey, M. S., Nguyen, T., DiLeone, R. J. & Schafe, G. E. The neuronal PAS domain protein 4 (Npas4) is required for new and reactivated fear memories. PLoS ONE 6, e23760 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Ramamoorthi, K. et al. Npas4 regulates a transcriptional program in CA3 required for contextual memory formation. Science 334, 1669–1675 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Coutellier, L., Beraki, S., Ardestani, P. M., Saw, N. L. & Shamloo, M. Npas4: a neuronal transcription factor with a key role in social and cognitive functions relevant to developmental disorders. PLoS ONE. 7, e46604 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. McNulty, S. E. et al. Differential roles for Nr4a1 and Nr4a2 in object location versus object recognition long-term memory. Learn. Mem. 19, 588–592 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Woolf, C. J. & Salter, M. W. Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1769 (2000).

    CAS  PubMed  Google Scholar 

  147. Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Russo, S. J. et al. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 33, 267–276 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Luscher, C. & Malenka, R. C. Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling. Neuron 69, 650–663 (2011).

    PubMed  PubMed Central  Google Scholar 

  150. Kauer, J. A. Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu. Rev. Physiol. 66, 447–475 (2004).

    CAS  PubMed  Google Scholar 

  151. Ma, W., Zheng, W. H., Powell, K., Jhamandas, K. & Quirion, R. Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: an in vitro and in vivo study. Eur. J. Neurosci. 14, 1091–1104 (2001).

    CAS  PubMed  Google Scholar 

  152. Ji, R. R. & Rupp, F. Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J. Neurosci. 17, 1776–1785 (1997).

    CAS  PubMed  Google Scholar 

  153. Geranton, S. M., Morenilla-Palao, C. & Hunt, S. P. A role for transcriptional repressor methyl-CpG-binding protein 2 and plasticity-related gene serum- and glucocorticoid-inducible kinase 1 in the induction of inflammatory pain states. J. Neurosci. 27, 6163–6173 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Vardeh, D. et al. COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice. J. Clin. Invest. 119, 287–294 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Luo, Z., Volkow, N. D., Heintz, N., Pan, Y. & Du, C. Acute cocaine induces fast activation of D1 receptor and progressive deactivation of D2 receptor striatal neurons: in vivo optical microprobe [Ca2+]i imaging. J. Neurosci. 31, 13180–13190 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Deng, J. V. et al. MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants. Nature Neurosci. 13, 1128–1136 (2010).

    CAS  PubMed  Google Scholar 

  157. Im, H. I., Hollander, J. A., Bali, P. & Kenny, P. J. MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nature Neurosci. 13, 1120–1127 (2010).

    CAS  PubMed  Google Scholar 

  158. Levine, A. A. et al. CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum. Proc. Natl Acad. Sci. USA 102, 19186–19191 (2005).

    CAS  PubMed  Google Scholar 

  159. DiNieri, J. A. et al. Altered sensitivity to rewarding and aversive drugs in mice with inducible disruption of cAMP response element-binding protein function within the nucleus accumbens. J. Neurosci. 29, 1855–1859 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Malvaez, M., Mhillaj, E., Matheos, D. P., Palmery, M. & Wood, M. A. CBP in the nucleus accumbens regulates cocaine-induced histone acetylation and its critical for cocaine-associated behaviors. J. Neurosci. 31, 16941–16948 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Ziviani, E. et al. Ryanodine receptor-2 upregulation and nicotine-mediated plasticity. EMBO J. 30, 194–204 (2011).

    CAS  PubMed  Google Scholar 

  162. Hiroi, N. et al. FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects. Proc. Natl Acad. Sci. USA 94, 10397–10402 (1997).

    CAS  PubMed  Google Scholar 

  163. McClung, C. A. & Nestler, E. J. Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nature Neurosci. 6, 1208–1215 (2003).

    CAS  PubMed  Google Scholar 

  164. Saffen, D. W. et al. Convulsant-induced increase in transcription factor messenger RNAs in rat brain. Proc. Natl Acad. Sci. USA 85, 7795–7799 (1988).

    CAS  PubMed  Google Scholar 

  165. French, P. J. et al. Seizure-induced gene expression in area CA1 of the mouse hippocampus. Eur. J. Neurosci. 14, 2037–2041 (2001).

    CAS  PubMed  Google Scholar 

  166. Newton, S. S. et al. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J. Neurosci. 23, 10841–10851 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Wang, H. et al. Chronic neuropathic pain is accompanied by global changes in gene expression and shares pathobiology with neurodegenerative diseases. Neuroscience 114, 529–546 (2002).

    CAS  PubMed  Google Scholar 

  168. Xiao, H. S. et al. Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc. Natl Acad. Sci. USA 99, 8360–8365 (2002).

    CAS  PubMed  Google Scholar 

  169. Lacroix-Fralish, M. L., Tawfik, V. L., Tanga, F. Y., Spratt, K. F. & DeLeo, J. A. Differential spinal cord gene expression in rodent models of radicular and neuropathic pain. Anesthesiology 104, 1283–1292 (2006).

    CAS  PubMed  Google Scholar 

  170. Lehrmann, E. et al. Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenom. J. 3, 27–40 (2003).

    CAS  Google Scholar 

  171. Albertson, D. N. et al. Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J. Neurochem. 88, 1211–1219 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Mash, D. C. et al. Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS ONE 2, e1187 (2007).

    PubMed  PubMed Central  Google Scholar 

  173. Freeman, W. M. et al. Persistent alterations in mesolimbic gene expression with abstinence from cocaine self-administration. Neuropsychopharmacology 33, 1807–1817 (2008).

    CAS  PubMed  Google Scholar 

  174. Tan, Y.-W., Zhang, S.-J., Hoffmann, T. & Bading, H. Increasing levels of wild-type CREB up-regulates several activity-regulated inhibitor of death (AID) genes and promotes neuronal survival. BMC Neurosci. 13, 48 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Bengtson, C. P., Dick, O. & Bading, H. A quantitative method to assess extrasynaptic NMDA receptor function in the protective effect of synaptic activity against neurotoxicity. BMC Neurosci. 9, 11 (2008).

    PubMed  PubMed Central  Google Scholar 

  176. Rossi, D. J., Oshima, T. & Attwell, D. Glutamate release in severe brain ischaemia is mainly by reverse uptake. Nature 403, 316–321 (2000).

    CAS  PubMed  Google Scholar 

  177. Angulo, M. C., Kozlov, A. S., Charpak, S. & Audinat, E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J. Neurosci. 24, 6920–6927 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Fellin, T. et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron. 43, 729–743 (2004).

    CAS  PubMed  Google Scholar 

  179. Le Meur, K., Galante, M., Angulo, M. C. & Audinat, E. Tonic activation of NMDA receptors by ambient glutamate of non-synaptic origin in the rat hippocampus. J. Physiol. 580, 373–383 (2007).

    CAS  PubMed  Google Scholar 

  180. Hamilton, N. B. & Attwell, D. Do astrocytes really exocytose neurotransmitters? Nature Rev. Neurosci. 11, 227–238 (2010).

    CAS  Google Scholar 

  181. Panatier, A. et al. Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125, 775–784 (2006).

    CAS  PubMed  Google Scholar 

  182. Papouin, T. et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 150, 633–646 (2012).

    CAS  PubMed  Google Scholar 

  183. Fan, M. M., Fernandes, H. B., Zhang, L. Y., Hayden, M. R. & Raymond, L. A. Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease. J. Neurosci. 27, 3768–3779 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Fan, M. M. & Raymond, L. A. N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease. Prog. Neurobiol. 81, 272–293 (2007).

    CAS  PubMed  Google Scholar 

  185. Okamoto, S. et al. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nature Med. 15, 1407–1413 (2009).

    CAS  PubMed  Google Scholar 

  186. Milnerwood, A. J. et al. Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice. Neuron 65, 178–190 (2010).

    CAS  PubMed  Google Scholar 

  187. Li, S. et al. Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62, 788–801 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Li, S. et al. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J. Neurosci. 31, 6627–6638 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Bordji, K., Becerril-Ortega, J., Nicole, O. & Buisson, A. Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ss production. J. Neurosci. 30, 15927–15942 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Suberbielle, E. et al. Physiological brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nature Neurosci. 16, 613–621 (2013).

    CAS  PubMed  Google Scholar 

  191. Smart, F. M. & Halpain, S. Regulation of dendritic spine stability. Hippocampus 10, 542–554 (2000).

    CAS  PubMed  Google Scholar 

  192. Knobloch, M. & Mansuy, I. M. Dendritic spine loss and synaptic alterations in Alzheimer's disease. Mol. Neurobiol. 37, 73–82 (2008).

    CAS  PubMed  Google Scholar 

  193. Palop, J. J. & Mucke, L. Amyloid-β-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nature Neurosci. 13, 812–818 (2010).

    CAS  PubMed  Google Scholar 

  194. Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Med. 14, 837–842 (2008).

    CAS  PubMed  Google Scholar 

  195. Talantova, M. et al. Aβ induces astrocytic glutamte release, extrasynaptic NMDA receptor activation, and synapse loss. Proc. Natl Acad. Sci. USA 110, E2518–E2527 (2013).

    CAS  PubMed  Google Scholar 

  196. Ebert, D. H. & Greenberg, M. E. Activity dependent neuronal signalling and autism spectrum disorders. Nature 493, 327–337 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Lin, Y. et al. Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 455, 1198–1204 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Yun, J. et al. Neuronal Per Arnt Sim (PAS) domain protein 4 (Npas4) regulates neurite outgrowth and phosphorylation of synapsin I. J. Biol. Chem. 288, 2655–2664 (2013).

    CAS  PubMed  Google Scholar 

  199. Lipton, S. A. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nature Rev. Drug Discov. 5, 160–170 (2006).

    CAS  Google Scholar 

  200. Lee, S. T. et al. Memantine reduces striatal cell death with decreasing calpain level in 3-nitropropionic model of Huntington's disease. Brain Res. 1118, 199–207 (2006).

    CAS  PubMed  Google Scholar 

  201. Beister, A. et al. The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease. J. Neural. Transm. Suppl. 68, 117–122 (2004).

    CAS  Google Scholar 

  202. Cosman, K. M., Boyle, L. L. & Porsteinsson, A. P. Memantine in the treatment of mild-to-moderate Alzheimer's disease. Expert Opin. Pharmacother. 8, 203–214 (2007).

    CAS  PubMed  Google Scholar 

  203. Xia, P., Chen, H. S., Zhang, D. & Lipton, S. A. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J. Neurosci. 30, 11246–11250 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Maus, L., Dick, O., Bading, H., Spatz, J. P. & Fiammengo, R. Conjugation of peptides to the passivation shell of gold nanoparticles for targeting of cell-surface receptors. ACS Nano 4, 6617–6628 (2010).

    CAS  PubMed  Google Scholar 

  205. Murayama, M., Perez-Garci, E., Luscher, H. R. & Larkum, M. E. Fiberoptic system for recording dendritic calcium signals in layer 5 neocortical pyramidal cells in freely moving rats. J. Neurophysiol. 98, 1791–1805 (2007).

    PubMed  Google Scholar 

  206. Johannssen, H. C. & Helmchen, F. In vivo Ca2+ imaging of dorsal horn neuronal populations in mouse spinal cord. J. Physiol. 588, 3397–3402 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Lutcke, H. et al. Optical recording of neuronal activity with a genetically-encoded calcium indicator in anesthetized and freely moving mice. Front. Neural Circuits 4, 9 (2010).

    PubMed  PubMed Central  Google Scholar 

  208. Mamiya, N. et al. Brain region-specific gene expression activation required for reconsolidation and extinction of contextual fear memory. J. Neurosci. 29, 402–413 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Higazi, D. R. et al. Endothelin-1-stimulated InsP3-induced Ca2+ release is a nexus for hypertrophic signaling in cardiac myocytes. Mol. Cell 33, 472–482 (2009).

    CAS  PubMed  Google Scholar 

  210. Wu, G., Xie, X., Lu, Z.-H. & Ledeen, R. W. Sodium-calcium exchanger complexed with GM1 ganglioside in nuclear membrane transfers calcium from nucleoplasm to endoplasmic reticulum. Proc. Natl Acad. Sci. USA 106, 10829–10834 (2009).

    CAS  PubMed  Google Scholar 

  211. Dolmetsch, R. & Geschwind, D. H. The human brain in a dish: the promise of iPSC-derived neurons. Cell 145, 831–834 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Irvine, R. F. Nuclear lipid signaling. Nature Rev. Mol. Cell Biol. 4, 1–12 (2003).

    Google Scholar 

  213. O'Malley, K. L., Jong, Y. J., Gonchar, Y., Burkhalter, A. & Romano, C. Activation of metabotropic glutamate receptor mGlu5 on nuclear membranes mediates intranuclear Ca2+ changes in heterologous cell types and neurons. J. Biol. Chem. 278, 28210–28219 (2003).

    CAS  PubMed  Google Scholar 

  214. Kumar, V., Jong, Y. J. & O'Malley, K. L. Activated nuclear metabotropic glutamate receptor mGlu5 couples to nuclear Gq/11 proteins to generate inositol 1,4,5-trisphosphate-mediated nuclear Ca2+ release. J. Biol. Chem. 283, 14072–14083 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Mak, D. O. & Foskett, J. K. Single-channel inositol 1,4,5-trisphosphate receptor currents revealed by patch clamp of isolated Xenopus oocyte nuclei. J. Biol. Chem. 269, 29375–29378 (1994).

    CAS  PubMed  Google Scholar 

  216. Gerasimenko, O. V., Gerasimenko, J. V., Tepikin, A. V. & Petersen, O. H. ATP-dependent accumulation and inositol trisphosphate- or cyclic ADP-ribose-mediated release of Ca2+ from the nuclear envelope. Cell 80, 439–444 (1995).

    CAS  PubMed  Google Scholar 

  217. Humbert, J. P., Matter, N., Artault, J. C., Koppler, P. & Malviya, A. N. Inositol 1,4,5-trisphosphate receptor is located to the inner nuclear membrane vindicating regulation of nuclear calcium signaling by inositol 1,4,5-trisphosphate. Discrete distribution of inositol phosphate receptors to inner and outer nuclear membranes. J. Biol. Chem. 271, 478–485 (1996).

    CAS  PubMed  Google Scholar 

  218. Santella, L. & Kyozuka, K. Effects of 1-methyladenine on nuclear Ca2+ transients and meiosis resumption in starfish oocytes are mimicked by the nuclear injection of inositol 1,4,5-trisphosphate and cADP-ribose. Cell Calcium 22, 11–20 (1997).

    CAS  PubMed  Google Scholar 

  219. Marchenko, S. M., Yarotskyy, V., Kovalenko, T. N., Kostyuk, P. G. & Thomas, R. C. Spontaneously active and InsP3-activated ion channels in cell nuclei from rat cerebellar Purkinje and granule neurones. J. Physiol. 565, 897–910 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Echevarria, W., Leite, M. F., Guerra, M. T., Zipfel, W. R. & Nathanson, M. H. Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nature Cell Biol. 5, 440–446 (2003).

    CAS  PubMed  Google Scholar 

  221. Ribak, C. E. & Seress, L. Five types of basket cell in the hippocampal dentate gyrus: a combined Golgi and electron microscopic study. J. Neurocytol. 12, 577–597 (1983).

    CAS  PubMed  Google Scholar 

  222. Frotscher, M., Kraft, J. & Zorn, U. Fine structure of identified neurons in the primate hippocampus: a combined Golgi/EM study in the baboon. J. Comp. Neurol. 275, 254–270 (1988).

    CAS  PubMed  Google Scholar 

  223. Soriano, E., Nitsch, R. & Frotscher, M. Axo-axonic chandelier cells in the rat fascia dentata: Golgi-electron microscopy and immunocytochemical studies. J. Comp. Neurol. 293, 1–25 (1990).

    CAS  PubMed  Google Scholar 

  224. Honavar, M. & Lantos, P. L. Ultrastructural changes in the frontal cortex and hippocampus in the ageing marmoset. Mech. Ageing Dev. 41, 161–175 (1987).

    CAS  PubMed  Google Scholar 

  225. Lafarga, M. et al. Fos-like expression and nuclear size in osmotically stimulated supraoptic nucleus neurons. Neuroscience 50, 867–875 (1992).

    CAS  PubMed  Google Scholar 

  226. Borsello, T., Mottier, V., Castagne, V. & Clarke, P. G. Ultrastructure of retinal ganglion cell death after axotomy in chick embryos. J. Comp. Neurol. 453, 361–371 (2002).

    PubMed  Google Scholar 

  227. Dorsey, D. A. et al. Ultrastructural characterization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced cell death in embryonic dopaminergic neurons. Apoptosis 11, 535–544 (2006).

    CAS  PubMed  Google Scholar 

  228. Collings, D. A. et al. Plant nuclei can contain extensive grooves and invaginations. Plant Cell 12, 2425–2440 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Wittmann, M. et al. Synaptic activity induces dramatic changes in the geometry of the cell nucleus: interplay between nuclear structure, histone H3 phosphorylation and nuclear calcium signaling. J. Neurosci. 29, 14687–14700 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Queisser, G., Wiegert, S. & Bading, H. Structural dynamics of the cell nucleus: basis for morphology modulation of nuclear calcium signaling and gene transcription. Nucleus 2, 98–104 (2011).

    PubMed  PubMed Central  Google Scholar 

  231. Qiu, J. et al. Mitochondrial calcium uniporter Mcu controls excitotoxicity and is repressed by neuroprotective nuclear calcium signals. Nature Commun. 4, 2034 (2013).

    Google Scholar 

  232. Papadia, S. et al. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nature Neurosci. 11, 476–487 (2008).

    CAS  PubMed  Google Scholar 

  233. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    CAS  PubMed  Google Scholar 

  234. Hitosugi, T. et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol. Cell 44, 864–877 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Glancy, B. & Balaban, R. S. Role of mitochondrial Ca2+ in the regulation of cellular energetics. Biochemistry 51, 2959–2973 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Bengtson, C. P., Kaiser, M., Obermayer, J. & Bading, H. Calcium responses to synaptically activated bursts of action potentials and their synapse-independent replay in cultured networks of hippocampal neurons. Biochim. Biophys. Acta 1833, 1672–1679 (2013).

    CAS  PubMed  Google Scholar 

  237. Cheng, H. Y. et al. DREAM is a critical transcriptional repressor for pain modulation. Cell 108, 31–43 (2002).

    CAS  PubMed  Google Scholar 

  238. Fischer, A., Sananbenesi, F., Mungenast, A. & Tsai, L.-H. Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharm. Sci. 31, 605–617 (2010).

    CAS  PubMed  Google Scholar 

  239. Oliveira, A. M. & Bading, H. Calcium signaling in cognition and ageing-dependent cognitive decline. Biofactors 37, 168–174 (2011).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This Review is dedicated to my thesis advisor, W. Hasselbach and to E. Carafoli, both pioneers in the field of calcium signalling. I am very grateful to the many excellent young scientists who I have had the pleasure to work with over the years; without them it would not have been possible to establish the function of nuclear calcium in biological adaptations. I would like to thank the members of my laboratory for comments on the manuscript and in particular A. Hagenston-Hertle, B. Buchthal and C. P. Bengtson for their help with the design of the figures. The work in the author's laboratory is supported by the Deutsche Forschungsgemeinschaft, the Alexander von Humboldt Foundation and the European Research Council Advanced Grant.

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  1. Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, INF 364, Heidelberg, 69120, Germany

    Hilmar Bading

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Glossary

Long-term potentiation

A long-lasting (hours or days) increase in synaptic efficacy that is most commonly measured as the response of neurons to stimulation of their presynaptic afferents after a brief patterned stimulus (for example, a 1-s, 100-Hz stimulus).

Nuclear envelope

Two membranes (outer and inner) surrounding the cell nucleus; the outer membrane is continuous with the endoplasmic reticulum. The outer nuclear membrane is connected to the inner nuclear membrane at the nuclear pore complexes.

Nuclear pore complexes

Large multiprotein complexes that form channels in the nuclear envelope of a eukaryotic cell. Nuclear pore complexes span the inner and outer nuclear membranes and allow the exchange of ions, metabolites and macromolecules between the nucleus and the cytoplasm.

Excitatory postsynaptic potential

The depolarizing voltage response of a postsynaptic neuron to a neurotransmitter released by one or more afferent presynaptic terminals that moves the membrane potential towards the action potential threshold.

Electrotonic signal

A passively propagating electrical impulse. It differs from an action potential in that its spread of charge along a cellular membrane does not involve the activation of voltage-dependent transmembrane currents.

Histone acetyltransferase

(HAT). An enzyme that catalyses the addition of an acetyl group to specific lysine residues in histones. In general, increased levels of histone acetylation are associated with the activation of gene expression. Many HATs function as transcriptional co-activators.

Histone deacetylases

(HDACs). Enzymes that remove the acetyl groups from lysine residues that are located at the amino termini of histones. In general, decreased levels of histone acetylation are associated with the repression of gene expression.

EF hand calcium-binding domain

A highly conserved calcium-binding domain, comprising two helices (E and F after the fifth and sixth helices of parvalbumin) that are linked by a short acidic calcium-binding loop that coordinates the calcium ion in a pentagonal bipyramidal arrangement. EF hands are found in many calcium-binding proteins, including calmodulin.

Transcriptome

The complete set of RNA molecules produced by a cell or a population of cells at a given time point.

Acquired neuroprotection

A synaptic activity-driven and gene transcription-dependent enhancement of the ability of neurons to survive harmful conditions.

Memory consolidation

A molecular mechanism by which memories are converted into an enduring form. This process typically lasts for a few hours after learning and requires new protein synthesis.

Contextual fear conditioning

A hippocampus-dependent form of Pavlovian conditioning in which rodents learn to associate a specific spatial context with the administration of an aversive stimulus: for example, an electrical footshock. When re-exposed to the same environment, animals will demonstrate a fear response: for example, freezing.

Oxygen–glucose deprivation

An in vitro model of cerebral stroke in which cultured neurons or brain slices are exposed to media containing insufficient amounts of glucose and oxygen, which leads to cell death.

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Bading, H. Nuclear calcium signalling in the regulation of brain function. Nat Rev Neurosci 14, 593–608 (2013). https://doi.org/10.1038/nrn3531

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