Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Astrocyte calcium signaling: the third wave

Abstract

The discovery that transient elevations of calcium concentration occur in astrocytes, and release 'gliotransmitters' which act on neurons and vascular smooth muscle, led to the idea that astrocytes are powerful regulators of neuronal spiking, synaptic plasticity and brain blood flow. These findings were challenged by a second wave of reports that astrocyte calcium transients did not mediate functions attributed to gliotransmitters and were too slow to generate blood flow increases. Remarkably, the tide has now turned again: the most important calcium transients occur in fine astrocyte processes not resolved in earlier studies, and new mechanisms have been discovered by which astrocyte [Ca2+]i is raised and exerts its effects. Here we review how this third wave of discoveries has changed our understanding of astrocyte calcium signaling and its consequences for neuronal function.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The first wave.
Figure 2: The second wave controversies.
Figure 3: The third wave and the future.

References

  1. Bezzi, P. et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat. Neurosci. 7, 613–620 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Barres, B.A. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60, 430–440 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Fiacco, T.A., Agulhon, C. & McCarthy, K.D. Sorting out astrocyte physiology from pharmacology. Annu. Rev. Pharmacol. Toxicol. 49, 151–174 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Cornell-Bell, A.H., Finkbeiner, S.M., Cooper, M.S. & Smith, S.J. Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247, 470–473 (1990).

    Article  CAS  PubMed  Google Scholar 

  5. Dani, J.W., Chernjavsky, A. & Smith, S.J. Neuronal activity triggers calcium waves in hippocampal astrocyte networks. Neuron 8, 429–440 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Porter, J.T. & McCarthy, K.D. Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J. Neurosci. 16, 5073–5081 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Newman, E.A. & Zahs, K.R. Calcium waves in retinal glial cells. Science 275, 844–847 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang, X. et al. Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo. Nat. Neurosci. 9, 816–823 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Hirase, H., Qian, L., Barthó, P. & Buzsáki, G. Calcium dynamics of cortical astrocytic networks in vivo. PLoS Biol. 2, E96 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Nimmerjahn, A., Kirchhoff, F., Kerr, J.N. & Helmchen, F. Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo. Nat. Methods 1, 31–37 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Parpura, V. et al. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Nedergaard, M. Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263, 1768–1771 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Pasti, L., Volterra, A., Pozzan, T. & Carmignoto, G. Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J. Neurosci. 17, 7817–7830 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bezzi, P. et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, 281–285 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Parri, H.R., Gould, T.M. & Crunelli, V. Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation. Nat. Neurosci. 4, 803–812 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kang, J., Jiang, L., Goldman, S.A. & Nedergaard, M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat. Neurosci. 1, 683–692 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Newman, E.A. Propagation of intercellular calcium waves in retinal astrocytes and Müller cells. J. Neurosci. 21, 2215–2223 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Newman, E.A. Glial cell inhibition of neurons by release of ATP. J. Neurosci. 23, 1659–1666 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pryazhnikov, E. & Khiroug, L. Sub-micromolar increase in [Ca2+]i triggers delayed exocytosis of ATP in cultured astrocytes. Glia 56, 38–49 (2008).

    Article  PubMed  Google Scholar 

  22. Yang, Y. et al. Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc. Natl. Acad. Sci. USA 100, 15194–15199 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mothet, J.-P. et al. Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine. Proc. Natl. Acad. Sci. USA 102, 5606–5611 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Henneberger, C., Papouin, T., Oliet, S.H. & Rusakov, D.A. Long-term potentiation depends on release of D-serine from astrocytes. Nature 463, 232–236 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu, Q.Y., Schaffner, A.E., Chang, Y.H., Maric, D. & Barker, J.L. Persistent activation of GABAA receptor/Cl channels by astrocyte-derived GABA in cultured embryonic rat hippocampal neurons. J. Neurophysiol. 84, 1392–1403 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Kozlov, A.S., Angulo, M.C., Audinat, E. & Charpak, S. Target cell-specific modulation of neuronal activity by astrocytes. Proc. Natl. Acad. Sci. USA 103, 10058–10063 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee, S. et al. Channel-mediated tonic GABA release from glia. Science 330, 790–796 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Jiménez-González, C., Pirttimaki, T., Cope, D.W. & Parri, H.R. Non-neuronal, slow GABA signalling in the ventrobasal thalamus targets δ-subunit-containing GABA(A) receptors. Eur. J. Neurosci. 33, 1471–1482 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Beattie, E.C. et al. Control of synaptic strength by glial TNFα. Science 295, 2282–2285 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Allen, N.J. et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486, 410–414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Diniz, L.P. et al. Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling. Glia 62, 1917–1931 (2014).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Perea, G. & Araque, A. Properties of synaptically evoked astrocyte calcium signal reveal synaptic information processing by astrocytes. J. Neurosci. 25, 2192–2203 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. D'Ascenzo, M. et al. mGluR5 stimulates gliotransmission in the nucleus accumbens. Proc. Natl. Acad. Sci. USA 104, 1995–2000 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Araque, A., Sanzgiri, R.P., Parpura, V. & Haydon, P.G. Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J. Neurosci. 18, 6822–6829 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fiacco, T.A. & McCarthy, K.D. Intracellular astrocyte calcium waves in situ increase the frequency of spontaneous AMPA receptor currents in CA1 pyramidal neurons. J. Neurosci. 24, 722–732 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jourdain, P. et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat. Neurosci. 10, 331–339 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Perea, G. & Araque, A. Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317, 1083–1086 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Pascual, O. et al. Astrocytic purinergic signaling coordinates synaptic networks. Science 310, 113–116 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Zhang, J.M. et al. ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 40, 971–982 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Serrano, A., Haddjeri, N., Lacaille, J.-C. & Robitaille, R. GABAergic network activation of glial cells underlies hippocampal heterosynaptic depression. J. Neurosci. 26, 5370–5382 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Halassa, M.M. et al. Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61, 213–219 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat. Neurosci. 6, 43–50 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Mulligan, S.J. & MacVicar, B.A. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431, 195–199 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Gordon, G.R., Choi, H.B., Rungta, R.L., Ellis-Davies, G.C. & MacVicar, B.A. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456, 745–749 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468, 232–243 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Harris, J.J., Jolivet, R. & Attwell, D. Synaptic energy use and supply. Neuron 75, 762–777 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Loaiza, A., Porras, O.H. & Barros, L.F. Glutamate triggers rapid glucose transport stimulation in astrocytes as evidenced by real-time confocal microscopy. J. Neurosci. 23, 7337–7342 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gourine, A.V. et al. Astrocytes control breathing through pH-dependent release of ATP. Science 329, 571–575 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Oberheim, N.A. et al. Uniquely hominid features of adult human astrocytes. J. Neurosci. 29, 3276–3287 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Han, X. et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12, 342–353 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Carmignoto, G. & Haydon, P.G. Astrocyte calcium signaling and epilepsy. Glia 60, 1227–1233 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Hamby, M.E. et al. Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G-protein-coupled receptors. J. Neurosci. 32, 14489–14510 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rossi, D. et al. Defective tumor necrosis factor-alpha-dependent control of astrocyte glutamate release in a transgenic mouse model of Alzheimer disease. J. Biol. Chem. 280, 42088–42096 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Lee, W. et al. Enhanced Ca2+-dependent glutamate release from astrocytes of the BACHD Huntington's disease mouse model. Neurobiol. Dis. 58, 192–199 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bezzi, P. et al. CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nat. Neurosci. 4, 702–710 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Takano, T. et al. Astrocyte-mediated control of cerebral blood flow. Nat. Neurosci. 9, 260–267 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Cahoy, J.D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sun, W. et al. Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339, 197–200 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cai, Z., Schools, G.P. & Kimelberg, H.K. Metabotropic glutamate receptors in acutely isolated hippocampal astrocytes: developmental changes of mGluR5 mRNA and functional expression. Glia 29, 70–80 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Lavialle, M. et al. Structural plasticity of perisynaptic astrocyte processes involves ezrin and metabotropic glutamate receptors. Proc. Natl. Acad. Sci. USA 108, 12915–12919 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Patrushev, I., Gavrilov, N., Turlapov, V. & Semyanov, A. Subcellular location of astrocytic calcium stores favors extrasynaptic neuron-astrocyte communication. Cell Calcium 54, 343–349 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Sahlender, D.A., Savtchouk, I. & Volterra, A. What do we know about gliotransmitter release from astrocytes? Philos. Trans. R. Soc. Lond. B Biol. Sci. 369, 20130592 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fiacco, T.A. et al. Selective stimulation of astrocyte calcium in situ does not affect neuronal excitatory synaptic activity. Neuron 54, 611–626 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Petravicz, J., Fiacco, T.A. & McCarthy, K.D. Loss of IP3 receptor-dependent Ca2+ increases in hippocampal astrocytes does not affect baseline CA1 pyramidal neuron synaptic activity. J. Neurosci. 28, 4967–4973 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Agulhon, C., Fiacco, T.A. & McCarthy, K.D. Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling. Science 327, 1250–1254 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Navarrete, M. et al. Astrocytes mediate in vivo cholinergic-induced synaptic plasticity. PLoS Biol. 10, e1001259 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Takata, N. et al. Astrocyte calcium signaling transforms cholinergic modulation to cortical plasticity in vivo. J. Neurosci. 31, 18155–18165 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bonder, D.E. & McCarthy, K.D. Astrocytic Gq-GPCR-linked IP3R-dependent Ca2+ signaling does not mediate neurovascular coupling in mouse visual cortex in vivo. J. Neurosci. 34, 13139–13150 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Nizar, K. et al. In vivo stimulus-induced vasodilation occurs without IP3 receptor activation and may precede astrocytic calcium increase. J. Neurosci. 33, 8411–8422 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Petravicz, J., Boyt, K.M. & McCarthy, K.D. Astrocyte IP3R2-dependent Ca2+ signaling is not a major modulator of neuronal pathways governing behavior. Front. Behav. Neurosci. 8, 384 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Wang, F. et al. Photolysis of caged Ca2+ but not receptor-mediated Ca2+ signaling triggers astrocytic glutamate release. J. Neurosci. 33, 17404–17412 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shigetomi, E., Bowser, D.N., Sofroniew, M.V. & Khakh, B.S. Two forms of astrocyte calcium excitability have distinct effects on NMDA receptor-mediated slow inward currents in pyramidal neurons. J. Neurosci. 28, 6659–6663 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schummers, J., Yu, H. & Sur, M. Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science 320, 1638–1643 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Schulz, K. et al. Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex. Nat. Methods 9, 597–602 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Winship, I.R., Plaa, N. & Murphy, T.H. Rapid astrocyte calcium signals correlate with neuronal activity and onset of the hemodynamic response in vivo. J. Neurosci. 27, 6268–6272 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lalo, U. et al. Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol. 12, e1001747 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Santello, M., Bezzi, P. & Volterra, A. TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69, 988–1001 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Takano, T. et al. Receptor-mediated glutamate release from volume sensitive channels in astrocytes. Proc. Natl. Acad. Sci. USA 102, 16466–16471 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Li, D. et al. Lack of evidence for vesicular glutamate transporter expression in mouse astrocytes. J. Neurosci. 33, 4434–4455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Fujita, T. et al. Neuronal transgene expression in dominant-negative SNARE mice. J. Neurosci. 34, 16594–16604 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Sloan, S.A. & Barres, B.A. Looks can be deceiving: reconsidering the evidence for gliotransmission. Neuron 84, 1112–1115 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sultan, S. et al. Synaptic integration of adult-born hippocampal neurons is locally controlled by astrocytes. Neuron 88, 1–16 (2015).

    Article  CAS  Google Scholar 

  85. Su, M. et al. Expression specificity of GFAP transgenes. Neurochem. Res. 29, 2075–2093 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Araque, A., Li, N., Doyle, R.T. & Haydon, P.G. SNARE protein-dependent glutamate release from astrocytes. J. Neurosci. 20, 666–673 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jurado, S. et al. LTP requires a unique postsynaptic SNARE fusion machinery. Neuron 77, 542–558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Feldmann, A. et al. Transport of the major myelin proteolipid protein is directed by VAMP3 and VAMP7. J. Neurosci. 31, 5659–5672 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Moreau, K. et al. PICALM modulates autophagy activity and tau accumulation. Nat. Commun. 5, 4998 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Nett, W.J., Oloff, S.H. & McCarthy, K.D. Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity. J. Neurophysiol. 87, 528–537 (2002).

    Article  PubMed  Google Scholar 

  91. Grosche, J. et al. Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nat. Neurosci. 2, 139–143 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Nimmerjahn, A., Mukamel, E.A. & Schnitzer, M.J. Motor behavior activates Bergmann glial networks. Neuron 62, 400–412 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kanemaru, K. et al. In vivo visualization of subtle, transient, and local activity of astrocytes using an ultrasensitive Ca2+ indicator. Cell Reports 8, 311–318 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Shigetomi, E., Kracun, S., Sofroniew, M.V. & Khakh, B.S. A genetically targeted optical sensor to monitor calcium signals in astrocyte processes. Nat. Neurosci. 13, 759–766 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Shigetomi, E., Tong, X., Kwan, K.Y., Corey, D.P. & Khakh, B.S. TRPA1 channels regulate astrocyte resting calcium and inhibitory synapse efficacy through GAT-3. Nat. Neurosci. 15, 70–80 (2012).

    Article  CAS  Google Scholar 

  96. Di Castro, M.A. et al. Local Ca2+ detection and modulation of synaptic release by astrocytes. Nat. Neurosci. 14, 1276–1284 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Panatier, A. et al. Astrocytes are endogenous regulators of basal transmission at central synapses. Cell 146, 785–798 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Chen, T.-W. et al. Ultrasensitive fluorescent proteins for imaging neuronal activity. Nature 499, 295–300 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sibille, J., Zapata, J., Teillon, J. & Rouach, N. Astroglial calcium signaling displays short-term plasticity and adjusts synaptic efficacy. Front. Cell. Neurosci. 9, 189 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Srinivasan, R. et al. Ca2+ signaling in astrocytes from Ip3r2−/− mice in brain slices and during startle responses in vivo. Nat. Neurosci. 18, 708–717 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tang, W. et al. Stimulation-evoked Ca2+ signals in astrocytic processes at hippocampal CA3-CA1 synapses of adult mice are modulated by glutamate and ATP. J. Neurosci. 35, 3016–3021 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lind, B.L., Brazhe, A.R., Jessen, S.B., Tan, F.C.C. & Lauritzen, M.J. Rapid stimulus-evoked astrocyte Ca2+ elevations and hemodynamic responses in mouse somatosensory cortex in vivo. Proc. Natl. Acad. Sci. USA 110, E4678–E4687 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Otsu, Y. et al. Calcium dynamics in astrocyte processes during neurovascular coupling. Nat. Neurosci. 18, 210–218 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Hamilton, N. et al. Mechanisms of ATP- and glutamate-mediated calcium signaling in white matter astrocytes. Glia 56, 734–749 (2008).

    Article  PubMed  Google Scholar 

  105. Palygin, O., Lalo, U., Verkhratsky, A. & Pankratov, Y. Ionotropic NMDA and P2X1/5 receptors mediate synaptically induced Ca2+ signalling in cortical astrocytes. Cell Calcium 48, 225–231 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Newman, E.A. Calcium increases in retinal glial cells evoked by light-induced neuronal activity. J. Neurosci. 25, 5502–5510 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Pankratov, Y. & Lalo, U. Role for astroglial α1-adrenoreceptors in gliotransmission and control of synaptic plasticity in the neocortex. Front. Cell. Neurosci. 9, 230 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Bowser, D.N. & Khakh, B.S. Vesicular ATP is the predominant cause of intercellular calcium waves in astrocytes. J. Gen. Physiol. 129, 485–491 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Haustein, M.D. et al. Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway. Neuron 82, 413–429 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Doengi, M. et al. GABA uptake-dependent Ca2+ signaling in developing olfactory bulb astrocytes. Proc. Natl. Acad. Sci. USA 106, 17570–17575 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Duffy, S. & MacVicar, B.A. Adrenergic calcium signaling in astrocyte networks within the hippocampal slice. J. Neurosci. 15, 5535–5550 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Shelton, M.K. & McCarthy, K.D. Hippocampal astrocytes exhibit Ca2+-elevating muscarinic cholinergic and histaminergic receptors in situ. J. Neurochem. 74, 555–563 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Paukert, M. et al. Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82, 1263–1270 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ding, F. α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice. Cell Calcium 54, 387–394 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Chen, N. et al. Nucleus basalis-enabled stimulus-specific plasticity in the visual cortex is mediated by astrocytes. Proc. Natl. Acad. Sci. USA 109, E2832–E2841 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Thrane, A.S. et al. General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex. Proc. Natl. Acad. Sci. USA 109, 18974–18979 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Woo, D.H. et al. TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell 151, 25–40 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Park, H. et al. High glutamate permeability and distal localization of Best1 channel in CA1 hippocampal astrocyte. Mol. Brain 6, 54 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Beppu, K. et al. Optogenetic countering of glial acidosis suppresses glial glutamate release and ischemic brain damage. Neuron 81, 314–320 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Devaraju, P., Sun, M.Y., Myers, T.L., Lauderdale, K. & Fiacco, T.A. Astrocytic group I mGluR-dependent potentiation of astrocytic glutamate and potassium uptake. J. Neurophysiol. 109, 2404–2414 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Mashimo, M. et al. Inositol 1,4,5-trisphosphate signaling maintains the activity of glutamate uptake in Bergmann glia. Eur. J. Neurosci. 32, 1668–1677 (2010).

    Article  PubMed  Google Scholar 

  122. Kalandadze, A., Wu, Y. & Robinson, M.B. Protein kinase C activation decreases cell surface expression of the GLT-1 subtype of glutamate transporter. Requirement of a carboxyl-terminal domain and partial dependence on serine 486. J. Biol. Chem. 277, 45741–45750 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Murphy-Royal, C. et al. Surface diffusion of astrocytic glutamate transporters shapes synaptic transmission. Nat. Neurosci. 18, 219–226 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Iino, M. et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Bernardinelli, Y. et al. Activity-dependent structural plasticity of perisynaptic astrocytic domains promotes excitatory synapse stability. Curr. Biol. 24, 1679–1688 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Wang, F. et al. Astrocytes modulate neural network activity by Ca2+-dependent uptake of extracellular K+. Sci. Signal. 5, ra26 (2012).

    PubMed  PubMed Central  Google Scholar 

  127. Volterra, A., Liaudet, N. & Savtchouk, I. Astrocyte Ca2+ signalling: an unexpected complexity. Nat. Rev. Neurosci. 15, 327–335 (2014).

    Article  CAS  PubMed  Google Scholar 

  128. Rusakov, D.A. Disentangling calcium-driven astrocyte physiology. Nat. Rev. Neurosci. 16, 226–233 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Nimmerjahn, A. & Bergles, D.E. Large-scale recording of astrocyte activity. Curr. Opin. Neurobiol. 32, 95–106 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Li, W., Llopis, J., Whitney, M., Zlokarnik, G. & Tsien, R.Y. Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression. Nature 392, 936–941 (1998).

    Article  CAS  PubMed  Google Scholar 

  131. Min, R. & Nevian, T. Astrocyte signaling controls spike timing-dependent depression at neocortical synapses. Nat. Neurosci. 15, 746–753 (2012).

    Article  CAS  PubMed  Google Scholar 

  132. Navarrete, M. & Araque, A. Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. Neuron 68, 113–126 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Holmström, K.M. et al. Signalling properties of inorganic polyphosphate in the mammalian brain. Nat. Commun. 4, 1362 (2013).

    Article  PubMed  CAS  Google Scholar 

  134. Filosa, J.A. et al. Endothelin-mediated calcium responses in supraoptic nucleus astrocytes influence magnocellular neurosecretory firing activity. J. Neuroendocrinol. 24, 378–392 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Bernardinelli, Y. et al. Astrocytes display complex and localized calcium responses to single-neuron stimulation in the hippocampus. J. Neurosci. 31, 8905–8919 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Morquette, P. et al. An astrocyte-dependent mechanism for neuronal rhythmogenesis. Nat. Neurosci. 18, 844–854 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Wang, H.C. et al. Spontaneous activity of cochlear hair cells triggered by fluid secretion mechanism in adjacent support cells. Cell 163, 1348–1359 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank N. Hamilton, R. Jolivet, A. Krasnow and A. Mishra for comments on the manuscript. Supported by the Wellcome Trust and European Research Council.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David Attwell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bazargani, N., Attwell, D. Astrocyte calcium signaling: the third wave. Nat Neurosci 19, 182–189 (2016). https://doi.org/10.1038/nn.4201

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.4201

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing