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  • Review Article
  • Published:

Do astrocytes really exocytose neurotransmitters?

Key Points

  • Ca2+-dependent exocytosis of glutamate, D-serine and ATP from astrocytes has been proposed to add a novel layer of information processing to the nervous system. It is suggested that these 'gliotransmitters' alter neuronal excitability and transmitter release, and cause damage in pathological conditions.

  • Exocytosis of transmitters from cultured astrocytes is well established, and astrocytes in situ express the protein machinery needed to accumulate transmitters in vesicles and to release the vesicles. Various different-sized membrane compartments may mediate exocytosis from astrocytes.

  • However, when the intracellular Ca2+ concentration increases in astrocytes in situ, it is hard to be certain that the resulting transmitter release is from astrocytes rather than neurons.

  • Non-exocytotic transmitter release mechanisms also exist in astrocytes, and exocytosis is used to insert non-exocytotic release proteins into the surface membrane.

  • Establishing, first, the exact Ca2+ signal needed in astrocytes in situ to trigger transmitter release, second, what determines where transmitter is released and, third, the relative importance of exocytotic and non-exocytotic release mechanisms, would considerably advance our understanding of the role of astrocytes in information processing.

Abstract

In the past 20 years, an extra layer of information processing, in addition to that provided by neurons, has been proposed for the CNS. Neuronally evoked increases of the intracellular calcium concentration in astrocytes have been suggested to trigger exocytotic release of the 'gliotransmitters' glutamate, ATP and D-serine. These are proposed to modulate neuronal excitability and transmitter release, and to have a role in diseases as diverse as stroke, epilepsy, schizophrenia, Alzheimer's disease and HIV infection. However, there is intense controversy about whether astrocytes can exocytose transmitters in vivo. Resolving this issue would considerably advance our understanding of brain function.

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Figure 1: Proposed functional effects of glutamate, D-serine and ATP release from astrocytes.
Figure 2: Methods for evoking or inhibiting Ca2+-dependent transmitter release from astrocytes.
Figure 3: Proteins proposed to mediate exocytosis from neurons and astrocytes.
Figure 4: Non-exocytotic and hybrid release mechanisms for neurotransmitters.
Figure 5: Membrane trafficking steps that are Ca2+- and TeNT-sensitive.

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References

  1. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Attwell, D. Glia and neurons in dialogue. Nature 369, 707–708 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. 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 

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

    Article  CAS  PubMed  Google Scholar 

  8. Parpura, V., Fang, Y., Basarsky, T., Jahn, R. & Haydon, P. Expression of synaptobrevin II, cellubrevin and syntaxin but not SNAP-25 in cultured astrocytes. FEBS Lett. 377, 489–492 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Hepp, R. et al. Cultured glial cells express the SNAP-25 analogue SNAP-23. Glia 27, 181–187 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Newman, E. A. Propagation of intercellular calcium waves in retinal astrocytes and Müller cells. J. Neurosci. 21, 2215–2223 (2001). An elegant demonstration of the spread of Ca2+ waves through astrocytes in situ and the release of ATP by these waves.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. 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). This study established the potential importance of exocytotic release of D -serine by astrocytes for regulating neuronal NMDA receptor activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  14. 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 

  15. 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 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. Jourdain, P. et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nature Neurosci. 10, 331–339 (2007). This study suggests that glutamate released from astrocyte vesicles located near presynaptic terminals promotes neuronal transmitter release by acting on presynaptic NMDA receptors.

    Article  CAS  PubMed  Google Scholar 

  21. Perea, G. & Araque, A. Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317, 1083–1086 (2007). The data presented suggest that vesicular glutamate release evoked by uncaging Ca2+ in astrocytes promotes neuronal transmitter release by acting on presynaptic mGluRs.

    Article  CAS  PubMed  Google Scholar 

  22. Andersson, M., Blomstrand, F. & Hanse, E. Astrocytes play a critical role in transient heterosynaptic depression in the rat hippocampal CA1 region. J. Physiol. 585, 843–852 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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 

  24. Coco, S. et al. Storage and release of ATP from astrocytes in culture. J. Biol. Chem. 278, 1354–1362 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. Pascual, O. et al. Astrocytic purinergic signaling coordinates synaptic networks. Science 310, 113–116 (2005). This paper shows that expression of a dominant negative SNARE in astrocytes, to suppress ATP release and downstream adenosine formation, leads to enhanced synaptic transmission.

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. Pangrsic, T. et al. Exocytotic release of ATP from cultured astrocytes. J. Biol. Chem. 282, 28749–28758 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Tsai, G., Yang, P., Chung, L. C., Lange, N. & Coyle, J. T. D-serine added to antipsychotics for the treatment of schizophrenia. Biol. Psychiatry 44, 1081–1089 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Agulhon, C. et al. What is the role of astrocyte calcium in neurophysiology? Neuron 59, 932–946 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 

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

    Article  CAS  Google Scholar 

  34. Tian, G.-F. et al. An astrocytic basis of epilepsy. Nature Med. 11, 973–981 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Fellin, T., Gomez-Gonzalo, M., Gobbo, S., Carmignoto, G. & Haydon, P. G. Astrocyte glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices. J. Neurosci. 26, 9312–9322 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Mothet, J. P. et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc. Natl Acad. Sci. USA 97, 4926–4931 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wolosker, H., Blackshaw, S. & Snyder, S. H. Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate/N-methyl-D-aspartate neurotransmission. Proc. Natl Acad. Sci. USA 96, 13409–13414 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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 

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

    Article  CAS  PubMed  Google Scholar 

  42. Isaacson, J. S., Solis, J. M. & Nicoll, R. A. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 10, 165–175 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Zhang, Q. et al. Fusion-related release of glutamate from astrocytes. J. Biol. Chem. 279, 12724–12733 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. 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 

  46. Bramham, C. R., Torp, R., Zhang, N., Storm-Mathisen, J. & Ottersen, O. P. Distribution of glutamate-like immunoreactivity in excitatory hippocampal pathways: a semiquantitative electron microscopic study in rats. Neuroscience 39, 405–417 (1990).

    Article  CAS  PubMed  Google Scholar 

  47. Clements, J. D. Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends Neurosci. 19, 163–171 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Dzubay, J. A. & Jahr, C. E. The concentration of synaptically released glutamate outside of the climbing fiber–Purkinje cell synaptic cleft. J. Neurosci. 19, 5265–5274 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Attwell, D. & Gibb, A. Neuroenergetics and the kinetic design of excitatory synapses. Nature Rev. Neurosci. 6, 841–849 (2005).

    Article  CAS  Google Scholar 

  50. Kartvelishvily, E., Shleper, M., Balan, L., Dumin, E. & Wolosker, H. Neuron-derived D-serine release provides a novel means to activate N-methyl-D-aspartate receptors. J. Biol. Chem. 281, 14151–14160 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Luján, R., Roberts, J. D., Shigemoto, R., Ohishi, H. & Somogyi, P. Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1 alpha, mGluR2 and mGluR5, relative to neurotransmitter release sites. J. Chem. Neuroanat. 13, 219–241 (1997).

    Article  PubMed  Google Scholar 

  52. Fiacco, T. A. et al. Selective stimulation of astrocyte calcium in situ does not affect neuronal excitatory synaptic activity. Neuron 54, 611–626 (2007). This paper challenges the idea that increases in [Ca2+]i in astrocytes lead to transmitter release, by expressing a receptor that increases [Ca2+]i in astrocytes and showing a lack of modulation of neuronal excitability or transmitter release.

    Article  CAS  PubMed  Google Scholar 

  53. 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 

  54. Zilberter, Y., Kaiser, K. M. & Sakmann, B. Dendritic GABA release depresses excitatory transmission between layer 2/3 pyramidal and bitufted neurons in rat neocortex. Neuron 24, 979–988 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Filosa, J. A. et al. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nature Neurosci. 9, 1397–1403 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. 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). This work shows that increases in astrocyte [Ca2+]i produced by different G protein-coupled receptors have different abilities to trigger transmitter release.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bowser, D. N. & Khakh, B. S. Two forms of single vesicle astrocyte exocytosis imaged with total internal reflection fluorescence microscopy. Proc. Natl Acad. Sci. USA 104, 4212–4217 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fonnum, F., Johnsen, A. & Hassel, B. Use of fluorocitrate and fluoroacetate in the study of brain metabolism. Glia 21, 106–113 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Bezzi, P. et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nature Neurosci. 7, 613–620 (2004). This study reports astrocyte vesicles in situ containing VGLUTs and VAMP3.

    Article  CAS  PubMed  Google Scholar 

  60. 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 

  61. Franke, H. et al. Changes in purinergic signaling after cerebral injury — involvement of glutamatergic mechanisms? Int. J. Dev. Neurosci. 24, 123–132 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Montana, V., Ni, Y., Hua, X. & Parpura, V. Vesicular glutamate transporter-dependent glutamate release from astrocytes. J. Neurosci. 24, 2633–2642 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fremeau, R. T. et al. The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate. Proc. Natl Acad. Sci. USA 99, 14488–14493 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li, D., Ropert, N., Koulakoff, A., Giaume, C. & Oheim, M. Lysosomes are the major vesicular compartment undergoing Ca2+-regulated exocytosis from cortical astrocytes. J. Neurosci. 28, 7648–7658 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Miyaji, T. et al. Identification of a vesicular aspartate transporter. Proc. Natl Acad. Sci. USA 105, 11720–11724 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pasti, L., Zonta, M., Pozzan, T., Vicini, S. & Carmignoto, G. Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate. J. Neurosci. 21, 477–484 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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 

  68. Takano, T. et al. Receptor-mediated glutamate release from volume sensitive channels in astrocytes. Proc. Natl Acad. Sci. USA 102, 16466–16471 (2005). This study shows that increases in astrocyte [Ca2+]i lead to cell swelling and glutamate release through swelling-activated channels.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cavelier, P. & Attwell, D. Neurotransmitter depletion by bafilomycin is promoted by vesicle turnover. Neurosci. Lett. 412, 95–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Domercq, M. et al. P2Y1 receptor-evoked glutamate exocytosis from astrocytes: control by tumor necrosis factor-α and prostaglandins. J. Biol. Chem. 281, 30684–30696 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Jahn, R. & Scheller, R. H. SNARES – engines for membrane fusion. Nature Rev. Mol. Cell Biol. 7, 631–643.

  72. Maienschein, V., Marxen, M., Volknandt, W. & Zimmerman, H. A plethora of presynaptic proteins associated with ATP-storing organelles in cultured astrocytes. Glia 26, 233–244 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Martineau, M., Galli, T., Baux, G. & Mothet, J.-P. Confocal imaging and tracking of the exocytotic routes for D-serine-mediated gliotransmission. Glia 56, 1271–1284 (2008).

    Article  PubMed  Google Scholar 

  74. Zhang, Q., Fukuda, M., Van Bockstaela, E., Pascual, O. & Haydon, P. G. Synaptotagmin IV regulates glial glutamate release. Proc. Natl Acad. Sci. USA 101, 9441–9446 (2004). An interesting analysis of a candidate Ca2+ sensor for astrocyte exocytosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. von Poser, C., Ichtchenko, K., Shao, X., Rizo, J. & Südhof, T. C. The evolutionary pressure to inactivate. A subclass of synaptotagmins with an amino acid substitution that abolishes Ca2+ binding. J. Biol. Chem. 272, 14314–14319 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Robinson, I. M., Ranjan, R. & Schwarz, T. L. Synaptotagmins I and IV promote transmitter release independently of Ca2+ binding in the C2A domain. Nature 418, 336–340 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Wang, C.-T. et al. Different domains of synaptotagmin control the choice between kiss-and-run and full fusion. Nature 424, 943–947 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Sugita, S. et al. Synaptotagmin VII as a plasma membrane Ca2+ sensor in exocytosis. Neuron 30, 459–473 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Fukuda, M., Kanno, E., Satoh, M., Saegusa, C. & Yamamoto, A. Synaptotagmin VII is targeted to dense-core vesicles and regulates their Ca2+ -dependent exocytosis in PC12 cells. J. Biol. Chem. 279, 52677–52684 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Parpura, V. & Haydon, P. G. Physiological astrocytic calcium levels stimulate glutamate release to modulate adjacent neurons. Proc. Natl Acad. Sci. USA 97, 8629–8634 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Parpura, V. et al. α-latrotoxin stimulates glutamate release from cortical astrocytes in cell culture. FEBS Lett. 360, 266–270 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Cali, C., Marchaland, J., Regazzi, R. & Bezzi, P. SDF-1α (CXCL12) triggers glutamate exocytosis from astrocytes on a millisecond time scale: imaging analysis at the single-vesicle level with TIRF microscopy. J. Neuroimmunol. 198, 82–91 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Zhang, Z. et al. Regulated ATP release from astrocytes through lysosome exocytosis. Nature Cell Biol. 9, 945–953 (2007). This study showed that astrocytes can exocytose ATP from lysosomes.

    Article  CAS  PubMed  Google Scholar 

  84. Chen, X., Wang, L., Zhou, Y., Zheng, L. H. & Zhou, Z. “Kiss-and-run” glutamate secretion in cultured and freshly isolated rat hippocampal astrocytes. J. Neurosci. 25, 9236–9243 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  86. Virginio, C., MacKenzie, A., Rassendren, F. A., North R. A. & Surprenant, A. Pore dilation of neuronal P2X channels. Nature Neurosci. 2, 315–321 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Duan, S. et al. P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J. Neurosci. 23, 1320–1328 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Suadicani, S. O., Brosnan, C. F. & Scemes, E. P2X7 receptors mediate ATP release and amplification of astrocytic intercellular Ca2+ signaling. J. Neurosci. 26, 1378–1385 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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 

  90. Thompson, R. J. & MacVicar, B. A. Connexin and pannexin hemichannels of neurons and astrocytes. Channels (Austin) 29 March 2008 [epub ahead of print].

    Google Scholar 

  91. Stout, C. E., Costantin, J. L., Naus, C. C. & Charles, A. C. Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J. Biol. Chem. 277, 10482–10488 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Contreras, J. E. et al. Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proc. Natl Acad. Sci. USA 99, 495–500 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Ye, Z. C., Wyeth, M. S., Baltan-Tekkok, S. & Ransom, B. R. Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J. Neurosci. 23, 3588–3596 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Thompson, R. J. et al. Activation of pannexin 1 hemichannels augments aberrant bursting in hippocampus. Science 322, 1555–1559 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Kimelberg, H. K, Goderie, S. K., Higman, S., Pang, S. & Waniewski, R. A. Swelling-induced release of glutamate, aspartate and taurine from astrocyte cultures. J. Neurosci. 10, 1583–1591 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Seki, Y., Feusterl, P. J., Keller, R. W. Jr, Tranmer, B. I. & Kimelberg, H. K. Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokainate and an anion channel blocker. Stroke 30, 433–440 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. O'Connor, E. R. & Kimelberg, H. K. Role of calcium in astrocyte volume regulation and in the release of ions and amino acids. J. Neurosci. 13, 2638–2650 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mongin, A. A. & Kimelberg, H. K. ATP regulates anion channel-mediated organic osmolyte release from cultured rat astrocytes via multiple Ca2+-sensitive mechanisms. Am. J. Physiol. Cell. Physiol. 288, C204–C213 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Ye, Z. C., Oberheim, N., Kettenmann, H. & Ransom, B. R. Pharmacological “cross-inhibition” of connexin hemichannels and swelling activated anion channels. Glia 57, 258–269 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Riveros, N., Fiedler, J., Lagos, N., Munoz, C. & Orrego, F. Glutamate in rat brain cortex synaptic vesicles: influence of the vesicle isolation procedure. Brain Res. 386, 405–408 (1986).

    Article  CAS  PubMed  Google Scholar 

  101. Stenovec, M. et al. Ca2+-dependent mobility of vesicles capturing anti-VGLUT1 antibodies. Exp. Cell Res. 313, 3809–3818 (2007).

    Article  CAS  PubMed  Google Scholar 

  102. Bekkers, J. M., Richerson, G. B. & Stevens, C. F. Origin of variability in quantal size in cultured hippocampal neurons and hippocampal slices. Proc. Natl Acad. Sci. USA 87, 45359–45362 (1990).

    Google Scholar 

  103. Stern, P., Edwards, F. A. & Sakmann, B. Fast and slow components of unitary EPSCs on stellate cells elicited by focal stimulation in slices of rat visual cortex. J. Physiol. 449, 247–278 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Jeftinija, S. D., Jeftinija, K. V. & Stefanovic, G. Cultured astrocytes express proteins involved in vesicular glutamate release. Brain Res. 750, 41–47 (1997).

    Article  CAS  PubMed  Google Scholar 

  105. Proux-Gillardeaux, V., Rudge, R. & Galli, T. The tetanus neurotoxin-sensitive and insensitive routes to and from the plasma membrane: fast and slow pathways? Traffic 6, 366–373 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Oishi, Y. et al. Role of VAMP-2, VAMP-7 and VAMP-8 in constitutive exocytosis from HSY cells. Histochem. Cell Biol. 125, 273–281 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Nedergaard, M., Takano, T. & Hansen, A. J. Beyond the role of glutamate as a neurotransmitter. Nature Rev. Neurosci. 3, 748–755 (2002).

    Article  CAS  Google Scholar 

  108. Galli, T. et al. Tetanus toxin-mediated cleavage of cellubrevin impairs exocytosis of transferrin receptor-containing vesicles in CHO cells. J. Cell Biol. 125, 1015–1024 (1994).

    Article  CAS  PubMed  Google Scholar 

  109. Stenovec, M., Kreft, M., Grilc, S., Pangrsic, T. & Zorec, R. EAAT2 density at the astrocyte plasma membrane and Ca2+-regulated exocytosis. Mol. Membr. Biol. 25, 203–215 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Randhawa, V. K. et al. VAMP2, but not VAMP3/cellubrevin, mediates insulin-dependent incorporation of GLUT4 into the plasma membrane of L6 myoblasts. Mol. Cell. Biol. 11, 2403–2417 (2000).

    Article  CAS  Google Scholar 

  111. Lu, W. et al. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Singh, B. B. et al. VAMP2-dependent exocytosis regulates plasma membrane insertion of TRPC3 channels and contributes to agonist-stimulated Ca2+ influx. Mol. Cell 15, 635–646 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Royle, S. J. & Murrell-Lagnado, R. Constitutive cycling: a general mechanism to regulate cell surface proteins. Bioessays 25, 39–46 (2003).

    Article  PubMed  CAS  Google Scholar 

  114. Furman, C. A. et al. Dopamine and amphetamine rapidly increase dopamine transporter trafficking to the surface: live-cell imaging using total internal reflection fluorescence microscopy. J. Neurosci. 29, 3328–3336 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lüthi, A. et al. Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF-GluR2 interaction. Neuron 24, 389–399 (1999).

    Article  PubMed  Google Scholar 

  116. Hay, J. C. Calcium: a fundamental regulator of intracellular membrane fusion? EMBO Rep. 8, 236–240 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Grasso, J. A., Bruno, M., Yates, A. A., Wei, L. T. & Epstein, P. M. Calmodulin-dependence of transferrin receptor recycling in rat reticulocytes. Biochem. J. 266, 261–272 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Knight, D. E. Calcium-dependent transferrin receptor recycling in bovine chromaffin cells. Traffic 3, 298–307 (2002).

    Article  PubMed  Google Scholar 

  119. Li, Y. et al. Regulation of insulin secretion and GLUT4 trafficking by the calcium sensor synaptotagmin VII. Biochem. Biophys. Res. Comm. 362, 658–664 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Marchaland, J. et al. Fast subplasma membrane Ca2+ transients control exo-endocytosis of synaptic like microvesicles in astrocytes. J. Neurosci. 28, 9122–9132 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Xu, J. et al. Glutamate-induced exocytosis of glutamate from astrocytes. J. Biol. Chem. 282, 24185–24197 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Kang, N., Xu, J., Xu, Q., Nedergaard, M. & Kang, J. Astrocytic glutamate release-induced transient depolarization and epileptiform discharges in hippocampal CA1 pyramidal neurons. J. Neurophysiol. 94, 4121–4130 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Jaiswal, J. K., Fix, M., Takano, T., Nedergaard, M. & Simon, S. M. Resolving vesicle fusion from lysis to monitor calcium-triggered lysosomal exocytosis in astrocytes. Proc. Natl Acad. Sci. USA 104, 14151–14156 (2007). This study showed that astrocytes can exocytose ATP from lysosomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hirase, H., Qian, L., Barthó, P. & Buzsáki, G. Calcium dynamics of cortical astrocyte networks in vivo. PLoS Biol. 2 e96 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  125. 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 

  126. 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 

  127. Nimmerjahn, A., Mukamel, E. A. & Schnitzer, N. J. Motor behaviour activates Bergmann glial networks. Neuron 62, 400–412 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 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 

  129. Andrews, N. W. & Chakrabarty, S. There's more to life than neurotransmission: the regulation of exocytosis by synaptotagmin VII. Trends Cell Biol. 15, 626–631 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. 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 

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Acknowledgements

We thank A. Gibb for carrying out simulations, and A. Volterra, P. Bezzi and V. Gundersen for vigorous debate on these issues. Our work is supported by the Wellcome Trust, the Fondation Leducq and the European Research Council.

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Glossary

Uncaging of Ca2+

Illumination of a chelator ('cage') that binds Ca2+ triggers release of the Ca2+ and a rise of the intracellular Ca2+ concentration in the illuminated cell.

Ifenprodil

A drug that blocks NMDA (N-methyl-D-aspartate) receptors containing NR2B subunits, which are found mainly in extrasynaptic locations.

SNARE

(Soluble N-ethylmaleimide-sensitive factor attachment protein receptor). A protein located in the vesicle membrane or plasma membrane that interacts with other SNAREs to pull the membranes together to promote fusion.

Time constant

The time for an exponential to decay to 1/e of its initial value.

Decaying exponential

A function used to describe the time course of a synaptic glutamate concentration transient, which has a certain amplitude at time zero and decays exponentially with a certain time constant thereafter.

Open probability

The fraction of time for which an ion channel is open.

Kiss-and-run exocytosis

A mode of transmitter release in which vesicles form only a transient fusion pore with the plasma membrane, rather than undergoing full fusion.

Sniffer cell

A cell expressing transmitter-sensing ion channels that detects as a change in membrane current the release of transmitter from other cells.

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Hamilton, N., Attwell, D. Do astrocytes really exocytose neurotransmitters?. Nat Rev Neurosci 11, 227–238 (2010). https://doi.org/10.1038/nrn2803

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