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Versatile control of synaptic circuits by astrocytes: where, when and how?

Nature Reviews Neuroscience volume 19, pages 729–743 (2018)Cite this article

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Abstract

Close structural and functional interactions of astrocytes with synapses play an important role in brain function. The repertoire of ways in which astrocytes can regulate synaptic transmission is complex so that they can both promote and dampen synaptic efficacy. Such contrasting effects raise questions regarding the determinants of these divergent astroglial functions. Recent findings provide insights into where, when and how astroglial regulation of synapses takes place by revealing major molecular and functional intrinsic heterogeneity as well as switches in astrocytes occurring during development or specific patterns of neuronal activity. Astrocytes may therefore be seen as boosters or gatekeepers of synaptic circuits depending on their intrinsic and transformative properties throughout life.

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Fig. 1: Diversity and plasticity of astroglial coverage of synapses.
Fig. 2: Structural and functional changes in astroglial perisynaptic processes during postnatal development.
Fig. 3: Activity-dependent synaptic regulation by purinergic gliotransmission.
Fig. 4: Dual role of gap junction-mediated astroglial networks in basal and network activity.

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References

  1. Bushong, E. A., Martone, M. E., Jones, Y. Z. & Ellisman, M. H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22, 183–192 (2002).

    CAS  PubMed  Google Scholar 

  2. Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).

    CAS  PubMed  Google Scholar 

  3. Chai, H. et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95, 531–549 (2017).This study uses multiple integrated approaches to provide evidence of neural circuit-specialized astrocytes and reveals molecular, morphological and functional astrocyte diversity in the adult hippocampus and striatum.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Martin-Fernandez, M. et al. Synapse-specific astrocyte gating of amygdala-related behavior. Nat. Neurosci. 20, 1540–1548 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Farmer, W. T. et al. Neurons diversify astrocytes in the adult brain through sonic hedgehog signaling. Science 351, 849–854 (2016).

    CAS  PubMed  Google Scholar 

  6. Lin, C. C. et al. Identification of diverse astrocyte populations and their malignant analogs. Nat. Neurosci. 20, 396–405 (2017).This study identifies molecularly and functionally diverse subpopulations of astrocytes in the adult brain, which play different roles in supporting synaptogenesis and have functional correlates in glioma.

    PubMed Central  Google Scholar 

  7. Ben Haim, L. & Rowitch, D. H. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 18, 31–41 (2016).

    PubMed  Google Scholar 

  8. Khakh, B. S. & Sofroniew, M. V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942–952 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Mishima, T. & Hirase, H. In vivo intracellular recording suggests that gray matter astrocytes in mature cerebral cortex and hippocampus are electrophysiologically homogeneous. J. Neurosci. 30, 3093–3100 (2010).

    CAS  PubMed  Google Scholar 

  10. Sibille, J., Dao Duc, K., Holcman, D. & Rouach, N. The neuroglial potassium cycle during neurotransmission: role of Kir4.1 channels. PLOS Comput. Biol. 11, e1004137 (2015).

    PubMed  PubMed Central  Google Scholar 

  11. Kelley, K. W. et al. Kir4.1-dependent astrocyte-fast motor neuron interactions are required for peak strength. Neuron 98, 306–319 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cui, Y. et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature 554, 323–327 (2018).

    CAS  Google Scholar 

  13. Tong, X. et al. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat. Neurosci. 17, 694–703 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ruminot, I. et al. NBCe1 mediates the acute stimulation of astrocytic glycolysis by extracellular K+. J. Neurosci. 31, 14264–14271 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Chesler, M. & Kraig, R. P. Intracellular pH of astrocytes increases rapidly with cortical stimulation. Am. J. Physiol. 253, R666–R670 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Chvátal, A., Pastor, A., Mauch, M., Syková, E. & Kettenmann, H. Distinct populations of identified glial cells in the developing rat spinal cord slice: ion channel properties and cell morphology. Eur. J. Neurosci. 7, 129–142 (1995).

    PubMed  Google Scholar 

  17. D’Ambrosio, R., Wenzel, J., Schwartzkroin, P. a, McKhann, G. M. & Janigro, D. Functional specialization and topographic segregation of hippocampal astrocytes. J. Neurosci. 18, 4425–4438 (1998).

    PubMed  PubMed Central  Google Scholar 

  18. Zhou, M. & Kimelberg, H. K. Freshly isolated astrocytes from rat hippocampus show two distinct current patterns and different [K+]o uptake capabilities. J. Neurophysiol. 84, 2746–2757 (2000).

    CAS  PubMed  Google Scholar 

  19. Zhong, S. et al. Electrophysiological behavior of neonatal astrocytes in hippocampal stratum radiatum. Mol. Brain 9, 34 (2016).

    PubMed  PubMed Central  Google Scholar 

  20. Du, Y. et al. Freshly dissociated mature hippocampal astrocytes exhibit passive membrane conductance and low membrane resistance similarly to syncytial coupled astrocytes. J. Neurophysiol. 113, 3744–3750 (2015).

    PubMed  PubMed Central  Google Scholar 

  21. Schools, G. P., Zhou, M. & Kimelberg, H. K. Development of gap junctions in hippocampal astrocytes: evidence that whole cell electrophysiological phenotype is an intrinsic property of the individual cell. J. Neurophysiol. 96, 1383–1392 (2006).

    PubMed  Google Scholar 

  22. Pannasch, U. et al. Astroglial networks scale synaptic activity and plasticity. Proc. Natl Acad. Sci. USA 108, 8467–8472 (2011).

    CAS  PubMed  Google Scholar 

  23. Hwang, E. M. et al. A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes. Nat. Commun. 5, 3227 (2014).

    PubMed  Google Scholar 

  24. Zhou, M. et al. TWIK-1 and TREK-1 are potassium channels contributing significantly to astrocyte passive conductance in rat hippocampal slices. J. Neurosci. 29, 8551–8564 (2009).

    CAS  PubMed  Google Scholar 

  25. Du, Y. et al. Genetic deletion of TREK-1 or TWIK-1/TREK-1 potassium channels does not alter the basic electrophysiological properties of mature hippocampal astrocytes in situ. Front. Cell. Neurosci. 10, 13 (2016).

    PubMed  PubMed Central  Google Scholar 

  26. Diamond, J. S. S., Bergles, D. E. E. & Jahr, C. E. E. Glutamate release monitored with astrocyte transporter currents during LTP. Neuron 21, 425–433 (1998).

    CAS  PubMed  Google Scholar 

  27. Luscher, C. et al. Monitoring glutamate release during LTP with glial transporter currents. Neuron 21, 435–441 (1998).

    CAS  PubMed  Google Scholar 

  28. Israel, J. M., Schipke, C. G., Ohlemeyer, C., Theodosis, D. T. & Kettenmann, H. GABAA receptor-expressing astrocytes in the supraoptic nucleus lack glutamate uptake and receptor currents. Glia 44, 102–110 (2003).

    PubMed  Google Scholar 

  29. de Vivo, L., Melone, M., Rothstein, J. D. & Conti, F. GLT-1 promoter activity in astrocytes and neurons of mouse hippocampus and somatic sensory cortex. Front. Neuroanat. 3, 31 (2010).

    PubMed  PubMed Central  Google Scholar 

  30. Rollenhagen, A. et al. Structural determinants of transmission at large hippocampal mossy fiber synapses. J. Neurosci. 27, 10434–10444 (2007).

    CAS  PubMed  Google Scholar 

  31. Lee, S. H., Kim, W. T., Cornell-Bell, A. H. & Sontheimer, H. Astrocytes exhibit regional specificity in gap-junction coupling. Glia 11, 315–325 (1994).

    CAS  PubMed  Google Scholar 

  32. Blomstrand, F., Åberg, N. D., Eriksson, P. S., Hansson, E. & Rönnbäck, L. Extent of intercellular calcium wave propagation is related to gap junction permeability and level of connexin-43 expression in astrocytes in primary cultures from four brain regions. Neuroscience 92, 255–265 (1999).

    CAS  PubMed  Google Scholar 

  33. Pannasch, U. & Rouach, N. Emerging role for astroglial networks in information processing: from synapse to behavior. Trends Neurosci. 36, 405–417 (2013).

    CAS  PubMed  Google Scholar 

  34. Chever, O., Dossi, E., Pannasch, U., Derangeon, M. & Rouach, N. Astroglial networks promote neuronal coordination. Sci. Signal. 9, ra6 (2016).

    PubMed  Google Scholar 

  35. Houades, V., Koulakoff, A., Ezan, P., Seif, I. & Giaume, C. Gap junction-mediated astrocytic networks in the mouse barrel cortex. J. Neurosci. 28, 5207–5217 (2008).

    CAS  PubMed  Google Scholar 

  36. Roux, L., Benchenane, K., Rothstein, J. D., Bonvento, G. & Giaume, C. Plasticity of astroglial networks in olfactory glomeruli. Proc. Natl Acad. Sci. USA 108, 18442–18446 (2011).

    CAS  PubMed  Google Scholar 

  37. Jayant, K. et al. Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes. Nat. Nanotechnol. 12, 335–342 (2017).

    CAS  PubMed  Google Scholar 

  38. Shigetomi, E. et al. Imaging calcium microdomains within entire astrocyte territories and endfeet with GCaMPs expressed using adeno-associated viruses. J. Gen. Physiol. 141, 633–647 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Paukert, M. et al. Norepinephrine controls astroglial responsiveness to local circuit activity. Neuron 82, 1263–1270 (2014).This pioneering study shows in vivo that locomotion triggers global and correlated Ca 2+ signalling in astroglial networks from multiple brain regions via noradrenaline, which primes astrocytes to respond to local neuronal activity.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  43. Schipke, C. G., Haas, B. & Kettenmann, H. Astrocytes discriminate and selectively respond to the activity of a aubpopulation of neurons within the barrel cortex. Cereb. Cortex 18, 2450–2459 (2008).

    PubMed  Google Scholar 

  44. Martín, R., Bajo-Grañeras, R., Moratalla, R., Perea, G. & Araque, A. Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Science 349, 730–734 (2015).

    PubMed  Google Scholar 

  45. Takata, N. & Hirase, H. Cortical layer 1 and layer 2/3 astrocytes exhibit distinct calcium dynamics in vivo. PLOS ONE 3, e2525 (2008).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Nicoll, R. A. & Schmitz, D. Synaptic plasticity at hippocampal mossy fibre synapses. Nat. Rev. Neurosci. 6, 863–876 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  50. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ma, Z., Stork, T., Bergles, D. E. & Freeman, M. R. Neuromodulators signal through astrocytes to alter neural circuit activity and behaviour. Nature 539, 428–432 (2016).This study shows that Drosophila astrocytes display activity-dependent Ca 2+ signalling in vivo via the octopamine–tyramine receptors and the TRP channel Water witch, which modulate downstream dopaminergic neurons and drive multiple sensory-driven behaviours.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Bindocci, E. et al. Three-dimensional Ca2+ imaging advances understanding of astrocyte biology. Science 356, eaai8185 (2017).This pioneering study develops a new method providing in an individual astrocyte a 3D analysis of Ca 2+ activity, which unravels its heterogenous, local and 3D nature.

    PubMed  Google Scholar 

  54. Rose, C. R. & Verkhratsky, A. Glial ionic excitability: the role for sodium. Glia 64, 1609–1610 (2016).

    PubMed  Google Scholar 

  55. Verkhratsky, A., Trebak, M., Perocchi, F., Khananishvili, D. & Sekler, I. Crosslink of calcium and sodium signalling in health and disease. Exp. Physiol. 103, 157–159 (2017).

    Google Scholar 

  56. Bosworth, A. P. & Allen, N. J. The diverse actions of astrocytes during synaptic development. Curr. Opin. Neurobiol. 47, 38–43 (2017).

    CAS  PubMed  Google Scholar 

  57. Baldwin, K. T. & Eroglu, C. Molecular mechanisms of astrocyte-induced synaptogenesis. Curr. Opin. Neurobiol. 45, 113–120 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Buosi, A. S., Matias, I., Araujo, A. P. B., Batista, C. & Gomes, F. C. A. Heterogeneity in synaptogenic profile of astrocytes from different brain regions. Mol. Neurobiol. 55, 751–762 (2017).

    PubMed  Google Scholar 

  59. Zhou, M. Development of GLAST(+) astrocytes and NG2(+) glia in rat hippocampus CA1: mature astrocytes are electrophysiologically passive. J. Neurophysiol. 95, 134–143 (2005).

    PubMed  Google Scholar 

  60. Kunzelmann, P. et al. Late onset and increasing expression of the gap junction protein connexin30 in adult murine brain and long-term cultured astrocytes. Glia 25, 111–119 (1999).

    CAS  PubMed  Google Scholar 

  61. Rouach, N., Koulakoff, A., Abudara, V., Willecke, K. & Giaume, C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551–1555 (2008).

    CAS  PubMed  Google Scholar 

  62. Gosejacob, D. et al. Role of astroglial connexin30 in hippocampal gap junction coupling. Glia 59, 511–519 (2011).

    PubMed  Google Scholar 

  63. Wallraff, A. et al. The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J. Neurosci. 26, 5438–5447 (2006).

    CAS  PubMed  Google Scholar 

  64. Ghézali, G. et al. Connexin 30 controls astroglial polarization during postnatal brain development. Development 145, dev155275 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. Furuta, a, Rothstein, J. D. & Martin, L. J. Glutamate transporter protein subtypes are expressed differentially during rat CNS development. J. Neurosci. 17, 8363–8375 (1997).

    CAS  PubMed  Google Scholar 

  66. Minelli, A., Barbaresi, P., Reimer, R. J., Edwards, R. H. & Conti, F. The glial glutamate transporter GLT-1 is localized both in the vicinity of and at distance from axon terminals in the rat cerebral cortex. Neuroscience 108, 51–59 (2001).

    CAS  PubMed  Google Scholar 

  67. Tzingounis, A. V. & Wadiche, J. I. Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat. Rev. Neurosci. 8, 935–947 (2007).

    CAS  PubMed  Google Scholar 

  68. Duan, S., Anderson, C. M., Stein, B. A. & Swanson, R. A. Glutamate induces rapid upregulation of astrocyte glutamate transport and cell-surface expression of GLAST. J. Neurosci. 19, 10193–10200 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  70. Nakayama, R., Sasaki, T., Tanaka, K. F. & Ikegaya, Y. Subcellular calcium dynamics during juvenile development in mouse hippocampal astrocytes. Eur. J. Neurosci. 43, 923–932 (2016).

    PubMed  Google Scholar 

  71. Schools, G. P. & Kimelberg, H. K. mGluR3 and mGluR5 are the predominant metabotropic glutamate receptor mRNAs expressed in hippocampal astrocytes acutely isolated from young rats. J. Neurosci. Res. 58, 533–543 (1999).

    CAS  PubMed  Google Scholar 

  72. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  75. Petralia, R. S., Wang, Y. X., Niedzielski, A. S. & Wenthold, R. J. The metabotropic glutamate receptors, MGLUR2 and MGLUR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71, 949–976 (1996).

    CAS  PubMed  Google Scholar 

  76. Meier, S. D., Kafitz, K. W. & Rose, C. R. Developmental profile and mechanisms of GABA-induced calcium signaling in hippocampal astrocytes. Glia 56, 1127–1137 (2008).

    PubMed  Google Scholar 

  77. Ben-Ari, Y. Excitatory actions of gaba during development: the nature of the nurture. Nat. Rev. Neurosci. 3, 728–739 (2002).

    CAS  PubMed  Google Scholar 

  78. Pyka, M. et al. Chondroitin sulfate proteoglycans regulate astrocyte-dependent synaptogenesis and modulate synaptic activity in primary embryonic hippocampal neurons. Eur. J. Neurosci. 33, 2187–2202 (2011).

    PubMed  Google Scholar 

  79. Milev, P. et al. Differential regulation of expression of hyaluronan-binding proteoglycans in developing brain: aggrecan, versican, neurocan, and brevican. Biochem. Biophys. Res. Commun. 247, 207–212 (1998).

    CAS  PubMed  Google Scholar 

  80. Orlando, C., Ster, J., Gerber, U., Fawcett, J. W. & Raineteau, O. Perisynaptic chondroitin sulfate proteoglycans restrict structural plasticity in an integrin-dependent manner. J. Neurosci. 32, 18009–18017 (2012).

    CAS  PubMed  Google Scholar 

  81. De Vivo, L. et al. Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex. Nat. Commun. 4, 1484 (2013).

    PubMed  Google Scholar 

  82. Pizzorusso, T. et al. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251 (2002).

    CAS  Google Scholar 

  83. Brakebusch, C. et al. Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory. Mol. Cell. Biol. 22, 7417–7427 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Valenzuela, J. C. et al. Hyaluronan-based extracellular matrix under conditions of homeostatic plasticity. Phil. Trans. R. Soc. B 369, 20130606 (2014).

    PubMed  Google Scholar 

  85. Dziembowska, M. & Wlodarczyk, J. MMP9: a novel function in synaptic plasticity. Int. J. Biochem. Cell Biol. 44, 709–713 (2012).

    CAS  PubMed  Google Scholar 

  86. Nagy, V. Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J. Neurosci. 26, 1923–1934 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Frischknecht, R. et al. Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat. Neurosci. 12, 897–904 (2009).

    CAS  PubMed  Google Scholar 

  88. Evers, M. R. et al. Impairment of L-type Ca2+ channel-dependent forms of hippocampal synaptic plasticity in mice deficient in the extracellular matrix glycoprotein tenascin-C. J. Neurosci. 22, 7177–7194 (2002).

    CAS  PubMed  Google Scholar 

  89. Xiao, Z. C. et al. Tenascin-R is a functional modulator of sodium channel β subunits. J. Biol. Chem. 274, 26511–26517 (1999).

    CAS  PubMed  Google Scholar 

  90. Bukalo, O., Schachner, M. & Dityatev, A. Hippocampal metaplasticity induced by deficiency in the extracellular matrix glycoprotein tenascin-R. J. Neurosci. 27, 6019–6028 (2007).

    CAS  PubMed  Google Scholar 

  91. Bornstein, P. Matricellular proteins: an overview. J. Cell Commun. Signal. 3, 163–165 (2009).

    PubMed  PubMed Central  Google Scholar 

  92. Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).

    CAS  PubMed  Google Scholar 

  93. Xu, J., Xiao, N. & Xia, J. Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nat. Neurosci. 13, 22–24 (2010).

    CAS  PubMed  Google Scholar 

  94. Eroglu, C. et al. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139, 380–392 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 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).

    CAS  PubMed  Google Scholar 

  96. Park, J. et al. Central mechanisms mediating thrombospondin-4-induced pain states. J. Biol. Chem. 291, 13335–13348 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Yu, P., Gong, N., Kweon, T. D., Vo, B. & Luo, D. Gabapentin prevents synaptogenesis between sensory and spinal cord neurons induced by thrombospondin-4 acting on pre-synaptic Cavα2δ1 subunits and involving T-type Ca2+ channels. Br. J. Pharmacol. 175, 2348–2361 (2018).

    CAS  PubMed  Google Scholar 

  98. Chen, H., Herndon, M. E. & Lawler, J. The cell biology of thrombospondin-1. Matrix Biol. 19, 597–614 (2000).

    CAS  PubMed  Google Scholar 

  99. Mendus, D. et al. Thrombospondins 1 and 2 are important for afferent synapse formation and function in the inner ear. Eur. J. Neurosci. 39, 1256–1267 (2014).

    PubMed  PubMed Central  Google Scholar 

  100. Kucukdereli, H. et al. Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC. Proc. Natl Acad. Sci. USA 108, E440–E449 (2011).

    CAS  PubMed  Google Scholar 

  101. López-Murcia, F. J., Terni, B. & Llobet, A. SPARC triggers a cell-autonomous program of synapse elimination. Proc. Natl Acad. Sci. USA 112, 13366–13371 (2015).

    PubMed  Google Scholar 

  102. Theodosis, D. T., Poulain, D. A. & Oliet, S. H. R. Activity-dependent structural and functional plasticity of astrocyte-neuron interactions. Physiol. Rev. 88, 983–1008 (2008).

    CAS  PubMed  Google Scholar 

  103. Lippman Bell, J. J., Lordkipanidze, T., Cobb, N. & Dunaevsky, A. Bergmann glial ensheathment of dendritic spines regulates synapse number without affecting spine motility. Neuron Glia Biol. 6, 193–200 (2010).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  105. Chung, W.-S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Vannucci, S. J. & Simpson, I. A. Developmental switch in brain nutrient transporter expression in the rat. Am. J. Physiol. Endocrinol. Metab. 285, E1127–E1134 (2003).

    CAS  PubMed  Google Scholar 

  107. Booth, R. F. G., Patel, T. B. & Clark, J. B. The development of enzymes of energy metabolism in the brain of a precocial (guinea pig) and non-precocial (rat) species. J. Neurochem. 34, 17–25 (1980).

    CAS  PubMed  Google Scholar 

  108. Pellerin, L. et al. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55, 1251–1262 (2007).

    PubMed  Google Scholar 

  109. Sada, N., Lee, S., Katsu, T., Otsuki, T. & Inoue, T. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 347, 1362–1367 (2015).This paper provides evidence that the glycolysis pathway involving the LDH enzyme pathway influences neuronal activation states, with strong implications for epilepsy.

    CAS  PubMed  Google Scholar 

  110. Guzmán, M. & Blázquez, C. Is there an astrocyte–neuron ketone body shuttle? Trends Endocrinol. Metab. 12, 169–173 (2001).

    PubMed  Google Scholar 

  111. Juge, N. et al. Metabolic control of vesicular glutamate transport and release. Neuron 68, 99–112 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Leino, R. L., Gerhart, D. Z. & Drewes, L. R. Monocarboxylate transporter (MCT1) abundance in brains of suckling and adult rats: a quantitative electron microscopic immunogold study. Dev. Brain Res. 113, 47–54 (1999).

    CAS  Google Scholar 

  113. McKenna, M. C., Dienel, G. A., Sonnewald, U., Waagepetersen, H. S. & Schousboe, A. in Basic Neurochemistry 8th edn Ch. 11 (eds Brady, S. T., Siegel, G. J., Albers, R. W. & Price, L. D.) 200–231 (Academic Press, 2012).

  114. Morken, T.-S. et al. Altered astrocyte-neuronal interactions after hypoxia-ischemia in the neonatal brain in female and male rats. Stroke 45, 2777–2785 (2014).

    PubMed  Google Scholar 

  115. Friedman, H. V., Bresler, T., Garner, C. C. & Ziv, N. E. Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment. Neuron 27, 57–69 (2000).

    CAS  PubMed  Google Scholar 

  116. Washbourne, P., Bennett, J. E. & McAllister, A. K. Rapid recruitment of NMDA receptor transport packets to nascent synapses. Nat. Neurosci. 5, 751–759 (2002).

    CAS  PubMed  Google Scholar 

  117. Papouin, T., Dunphy, J. M., Tolman, M., Dineley, K. T. & Haydon, P. G. Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness. Neuron 94, 840–854 (2017).This study shows that brain states of wakefulness are influenced by oscillations of d -serine and that these variations are controlled by nicotinic signalling on astrocytes.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  119. 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).

    CAS  PubMed  Google Scholar 

  120. Covelo, A. & Araque, A. Neuronal activity determines distinct gliotransmitter release from a single astrocyte. eLife 7, e32237 (2018).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  122. 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).

    CAS  PubMed  Google Scholar 

  123. Liu, Q. -s., Xu, Q., Arcuino, G., Kang, J. & Nedergaard, M. From the cover: astrocyte-mediated activation of neuronal kainate receptors. Proc. Natl Acad. Sci. USA 101, 3172–3177 (2004).

    CAS  PubMed  Google Scholar 

  124. Panatier, A. & Robitaille, R. Astrocytic mGluR5 and the tripartite synapse. Neuroscience 323, 29–34 (2016).

    CAS  PubMed  Google Scholar 

  125. Stobart, J. L. et al. Cortical circuit activity evokes rapid astrocyte calcium signals on a similar timescale to neurons. Neuron 98, 726–735 (2018).

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

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Perea, G., Yang, A., Boyden, E. S. & Sur, M. Optogenetic astrocyte activation modulates response selectivity of visual cortex neurons in vivo. Nat. Commun. 5, 3262 (2014).

    PubMed  PubMed Central  Google Scholar 

  129. Benedetti, B., Matyash, V. & Kettenmann, H. Astrocytes control GABAergic inhibition of neurons in the mouse barrel cortex. J. Physiol. 589, 1159–1172 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 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).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Kurashige, H. & Sakai, Y. in Neural Information Processing — Lecture Notes in Computer Science Vol. 4232 (eds King, I., Wang, J., Chan, L.-W. & Wang, D. L.) 19–29 (Springer, 2006).

  133. Cohen, D. & Segal, M. Network bursts in hippocampal microcultures are terminated by exhaustion of vesicle pools. J. Neurophysiol. 106, 2314–2321 (2011).

    PubMed  Google Scholar 

  134. Staley, K. J., Longacher, M., Bains, J. S. & Yee, A. Presynaptic modulation of CA3 network activity. Nat. Neurosci. 1, 201–209 (1998).

    CAS  PubMed  Google Scholar 

  135. Ghézali, G., Dallérac, G. & Rouach, N. Perisynaptic astroglial processes: dynamic processors of neuronal information. Brain Struct. Funct. 221, 2427–2442 (2016).

    PubMed  Google Scholar 

  136. Nixdorf-Bergweiler, B. E., Albrecht, D. & Heinemann, U. Developmental changes in the number, size, and orientation of GFAP-positive cells in the CA1 region of rat hippocampus. Glia 12, 180–195 (1994).

    CAS  PubMed  Google Scholar 

  137. Anders, S. et al. Spatial properties of astrocyte gap junction coupling in the rat hippocampus. Phil. Trans. R. Soc. B 369, 20130600 (2014).

    PubMed  Google Scholar 

  138. Buhl, D. L. & Buzsáki, G. Developmental emergence of hippocampal fast-field “ripple” oscillations in the behaving rat pups. Neuroscience 134, 1423–1430 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Viola, G. G. et al. Morphological changes in hippocampal astrocytes induced by environmental enrichment in mice. Brain Res. 1274, 47–54 (2009).

    CAS  PubMed  Google Scholar 

  140. Saur, L. et al. Physical exercise increases GFAP expression and induces morphological changes in hippocampal astrocytes. Brain Struct. Funct. 219, 293–302 (2014).

    CAS  PubMed  Google Scholar 

  141. Mestriner, R. G. et al. Astrocyte morphology after ischemic and hemorrhagic experimental stroke has no influence on the different recovery patterns. Behav. Brain Res. 278, 257–261 (2015).

    PubMed  Google Scholar 

  142. Bernardinelli, Y., Muller, D. & Nikonenko, I. Astrocyte-synapse structural plasticity. Neural Plast. 2014, 232105 (2014).

    PubMed  PubMed Central  Google Scholar 

  143. Witcher, M. R., Kirov, S. A. & Harris, K. M. Plasticity of perisynaptic astroglia during synaptogenesis in the mature rat hippocampus. Glia 55, 13–23 (2007).

    PubMed  Google Scholar 

  144. Xu-Friedman, M. A. & Regehr, W. G. Ultrastructural contributions to desensitization at cerebellar mossy fiber to granule cell synapses. J. Neurosci. 23, 2182–2192 (2003).

    CAS  PubMed  Google Scholar 

  145. Xu-Friedman, M. A., Harris, K. M. & Regehr, W. G. Three-dimensional comparison of ultrastructural characteristics at depressing and facilitating synapses onto cerebellar Purkinje cells. J. Neurosci. 21, 6666–6672 (2001).

    CAS  PubMed  Google Scholar 

  146. Petrak, L. J., Harris, K. M. & Kirov, S. A. Synaptogenesis on mature hippocampal dendrites occurs via filopodia and immature spines during blocked synaptic transmission. J. Comp. Neurol. 484, 183–190 (2005).

    PubMed  Google Scholar 

  147. Harms, K. J. & Dunaevsky, A. Dendritic spine plasticity: looking beyond development. Brain Res. 1184, 65–71 (2007).

    CAS  PubMed  Google Scholar 

  148. Perez-Alvarez, A., Navarrete, M., Covelo, A., Martin, E. D. & Araque, A. Structural and functional plasticity of astrocyte processes and dendritic spine interactions. J. Neurosci. 34, 12738–12744 (2014).

    PubMed  Google Scholar 

  149. Genoud, C. et al. Plasticity of astrocytic coverage and glutamate transporter expression in adult mouse cortex. PLOS Biol. 4, e343 (2006).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  151. Lushnikova, I., Skibo, G., Muller, D. & Nikonenko, I. Synaptic potentiation induces increased glial coverage of excitatory synapses in CA1 hippocampus. Hippocampus 19, 753–762 (2009).

    PubMed  Google Scholar 

  152. Ostroff, L. E., Manzur, M. K., Cain, C. K. & Ledoux, J. E. Synapses lacking astrocyte appear in the amygdala during consolidation of Pavlovian threat conditioning. J. Comp. Neurol. 522, 2152–2163 (2014).

    PubMed  PubMed Central  Google Scholar 

  153. Bellesi, M., de Vivo, L., Tononi, G. & Cirelli, C. Effects of sleep and wake on astrocytes: clues from molecular and ultrastructural studies. BMC Biol. 13, 66 (2015).

    PubMed  PubMed Central  Google Scholar 

  154. Theodosis, D. T. Oxytocin-secreting neurons: a physiological model of morphological neuronal and glial plasticity in the adult hypothalamus. Front. Neuroendocrinol. 23, 101–135 (2002).

    CAS  PubMed  Google Scholar 

  155. Miyata, S. & Hatton, G. I. Activity-related, dynamic neuron-glial interactions in the hypothalamo-neurohypophysial system. Microsc. Res. Tech. 56, 143–157 (2002).

    CAS  PubMed  Google Scholar 

  156. Ventura, R. & Harris, K. M. Three-dimensional relationships between hippocampal synapses and astrocytes. J. Neurosci. 19, 6897–6906 (1999).

    CAS  PubMed  Google Scholar 

  157. Bernardinelli, Y., Nikonenko, I. & Muller, D. Structural plasticity: mechanisms and contribution to developmental psychiatric disorders. Front. Neuroanat. 8, 123 (2014).

    PubMed  PubMed Central  Google Scholar 

  158. Foley, J. et al. Astrocytic IP3/Ca2+ signaling modulates theta rhythm and REM sleep. Front. Neural Circuits 11, 3 (2017).

    PubMed  PubMed Central  Google Scholar 

  159. Bonansco, C. et al. Glutamate released spontaneously from astrocytes sets the threshold for synaptic plasticity. Eur. J. Neurosci. 33, 1483–1492 (2011).

    PubMed  Google Scholar 

  160. Shigetomi, E., Jackson-Weaver, O., Huckstepp, R. T., O’Dell, T. J. & Khakh, B. S. TRPA1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via constitutive d-serine release. J. Neurosci. 33, 10143–10153 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Sherwood, M. W. et al. Astrocytic IP3Rs: contribution to Ca2+ signalling and hippocampal LTP. Glia 65, 502–513 (2017).

    PubMed  Google Scholar 

  162. Andersson, M. & Hanse, E. Astrocytes impose postburst depression of release probability at hippocampal glutamate synapses. J. Neurosci. 30, 5776–5780 (2010).

    CAS  PubMed  Google Scholar 

  163. Chen, J. et al. Heterosynaptic long-term depression mediated by ATP released from astrocytes. Glia 61, 178–191 (2013).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  165. Tanaka, M. et al. Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol. Brain 6, 6 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 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).

    CAS  PubMed  Google Scholar 

  167. Poskanzer, K. E. & Yuste, R. Astrocytic regulation of cortical UP states. Proc. Natl Acad. Sci. USA 108, 18453–18458 (2011).

    CAS  PubMed  Google Scholar 

  168. Poskanzer, K. E. & Yuste, R. Astrocytes regulate cortical state switching in vivo. Proc. Natl Acad. Sci. USA 113, E2675–E2684 (2016).

    CAS  PubMed  Google Scholar 

  169. Wang, F., Xu, Q., Wang, W., Takano, T. & Nedergaard, M. Bergmann glia modulate cerebellar Purkinje cell bistability via Ca2+-dependent K+ uptake. Proc. Natl Acad. Sci. USA 109, 7911–7916 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the European Research Council (consolidator grant #683154), European Union (Marie Sklodowska-Curie Innovative Training Networks, EU-GliaPhD grant # H2020-MSCA-ITN-2016-722053) and Agence Nationale de la Recherche (grant #ANR-15-CE16-0001) to N.R., the Collège de France to G.D. and the Collège de France and Fyssen Foundation to J.Z.

Reviewer information

Nature Reviews Neuroscience thanks K. Murai, P. Haydon and the other anonymous reviewer for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Center for Interdisciplinary Research in Biology, Collège de France, CNRS UMR 7241, INSERM U1050, Labex Memolife, PSL Research University, Paris, France

    Glenn Dallérac, Jonathan Zapata & Nathalie Rouach

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  1. Glenn Dallérac
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  2. Jonathan Zapata
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The authors all contributed to the research, writing and reviewing of the manuscript. G.D. and N.R. edited the manuscript.

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Correspondence to Nathalie Rouach.

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Glossary

UP and DOWN states

Spontaneous alternation of neuronal membrane potential between two preferential levels corresponding to an active period of depolarization associated with sustained firing (UP state) and a quiescent period with hyperpolarized membrane potential (DOWN state).

Passive astrocytes

Functional subtype of astrocytes that present a linear current–voltage relationship.

Complex astrocytes

Functional subtype of astrocytes that display voltage-dependent currents.

Perisynaptic astroglial processes

(PAPs). Fine distal processes of astrocytes surrounding synaptic elements, integrating and processing synaptic information.

Mossy fibre synapses

Peculiar synapses with a giant presynaptic bouton possessing, on average, 25 active zones. These synapses occur in the hippocampus between dentate granule cells and CA3 pyramidal neurons as well as in the cerebellum, where inputs from several brain regions synapse onto granule cells.

GJ communication

Gap junction (GJ)-mediated direct electrical and metabolic coupling between adjacent cells allowing cytoplasmic exchanges of small molecules with a molecular mass below 1.5 kDa, including ions, neurotransmitters, second messengers or energy metabolites.

Polarity

Reorientation of CA1 striatum radiatum astrocyte stem processes polarizing perpendicularly to the pyramidal cell layer during postnatal maturation.

Matricellular proteins

Proteins that are secreted to the extracellular environment but do not play a structural role in this location and instead modulate cell functions by interacting with cell-surface receptors and structural elements of the matrix.

Glutamine–glutamate cycle

Metabolic pathway consisting of the recycling of glutamate released during synaptic transmission. Glutamate is taken up and metabolized into glutamine by astrocytes and then transported back to neurons as a precursor.

Astroglial synapse coverage

Ensheathment of synaptic structures by astroglial membranes that can vary with cell types, activity and physiological state.

Gliotransmitters

Neuroactive substances released by astrocytes such as glutamate, ATP or lactate.

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Dallérac, G., Zapata, J. & Rouach, N. Versatile control of synaptic circuits by astrocytes: where, when and how?. Nat Rev Neurosci 19, 729–743 (2018). https://doi.org/10.1038/s41583-018-0080-6

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