Regulation of synaptic connectivity by glia

Article metrics


The human brain contains more than 100 trillion (1014) synaptic connections, which form all of its neural circuits. Neuroscientists have long been interested in how this complex synaptic web is weaved during development and remodelled during learning and disease. Recent studies have uncovered that glial cells are important regulators of synaptic connectivity. These cells are far more active than was previously thought and are powerful controllers of synapse formation, function, plasticity and elimination, both in health and disease. Understanding how signalling between glia and neurons regulates synaptic development will offer new insight into how the nervous system works and provide new targets for the treatment of neurological diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The tripartite synapse.
Figure 2: Glial regulation of synaptic development.
Figure 3: Molecular pathways known to regulate axon pruning and synapse elimination by glia in invertebrates.
Figure 4: Regulation of synapse elimination in the mammalian CNS by the complement cascade.


  1. 1

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

  2. 2

    Chittajallu, R., Aguirre, A. & Gallo, V. NG2-positive cells in the mouse white and grey matter display distinct physiological properties. J. Physiol. (Lond.) 561, 109–122 (2004).

  3. 3

    Lin, S. C. & Bergles, D. E. Physiological characteristics of NG2-expressing glial cells. J. Neurocytol. 31, 537–549 (2002).

  4. 4

    Eroglu, C., Barres, B. A. & Stevens, B. in Structural and Functional Organization of the Synapse (eds Hell, J. W. & Ehlers, M. D.) 683–714 (Springer, 2008).

  5. 5

    Feng, Z. & Ko, C. P. Neuronal glia interactions at the vertebrate neuromuscular junction. Curr. Opin. Pharmacol. 7, 316–324 (2007).

  6. 6

    Bolton, M. M. & Eroglu, C. Look who is weaving the neural web: glial control of synapse formation. Curr. Opin. Neurobiol. 19, 491–497 (2009).

  7. 7

    Reichenbach, A., Derouiche, A. & Kirchhoff, F. Morphology and dynamics of perisynaptic glia. Brain Res. Rev. 63, 11–25 (2010).

  8. 8

    Doherty, J., Logan, M. A., Tasdemir, O. E. & Freeman, M. R. Ensheathing glia function as phagocytes in the adult Drosophila brain. J. Neurosci. 29, 4768–4781 (2009).

  9. 9

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

  10. 10

    Wang, X. et al. Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo . Nature Neurosci. 9, 816–823 (2006). This paper shows that the stimulation of whiskers increases the cytosolic Ca2+ concentration in astrocytes in the barrel cortex of adult mice. This is the first in vivo evidence that astrocytes respond to a presynaptic spillover of glutamate by increasing their cytosolic Ca2+ concentrations.

  11. 11

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

  12. 12

    Bergles, D. E., Roberts, J. D., Somogyi, P. & Jahr, C. E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405, 187–191 (2000). This is the first report of glutamate-mediated synaptic contacts and fast synaptic transmission between pyramidal neurons and OPCs in the mammalian hippocampus.

  13. 13

    Lin, S. C. et al. Climbing fiber innervation of NG2-expressing glia in the mammalian cerebellum. Neuron 46, 773–785 (2005).

  14. 14

    De Biase, L. M., Nishiyama, A. & Bergles, D. E. Excitability and synaptic communication within the oligodendrocyte lineage. J. Neurosci. 30, 3600–3611 (2010).

  15. 15

    Lin, S. C. & Bergles, D. E. Synaptic signaling between GABAergic interneurons and oligodendrocyte precursor cells in the hippocampus. Nature Neurosci. 7, 24–32 (2004).

  16. 16

    Zhang, Y. & Barres, B. A. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr. Opin. Neurobiol. 20, 588–594 (2010).

  17. 17

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

  18. 18

    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).

  19. 19

    Halassa, M. M., Fellin, T., Takano, H., Dong, J. H. & Haydon, P. G. Synaptic islands defined by the territory of a single astrocyte. J. Neurosci. 27, 6473–6477 (2007).

  20. 20

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

  21. 21

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

  22. 22

    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).

  23. 23

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

  24. 24

    Hirrlinger, J., Hulsmann, S. & Kirchhoff, F. Astroglial processes show spontaneous motility at active synaptic terminals in situ . Eur. J. Neurosci. 20, 2235–2239 (2004).

  25. 25

    Theodosis, D. T. et al. Oxytocin and estrogen promote rapid formation of functional GABA synapses in the adult supraoptic nucleus. Mol. Cell. Neurosci. 31, 785–794 (2006).

  26. 26

    Iino, M. et al. Glia–synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001). This paper shows that Ca2+-permeable AMPA receptors on glia are required for proper structural and functional relationships between Bergmann glia and glutamate-mediated synapses in the cerebellum.

  27. 27

    Haber, M., Zhou, L. & Murai, K. K. Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses. J. Neurosci. 26, 8881–8891 (2006).

  28. 28

    Nishida, H. & Okabe, S. Direct astrocytic contacts regulate local maturation of dendritic spines. J. Neurosci. 27, 331–340 (2007).

  29. 29

    Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y. & Pasquale, E. B. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nature Neurosci. 6, 153–160 (2003).

  30. 30

    Carmona, M. A., Murai, K. K., Wang, L., Roberts, A. J. & Pasquale, E. B. Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport. Proc. Natl Acad. Sci. USA 106, 12524–12529 (2009).

  31. 31

    Filosa, A. et al. Neuron–glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nature Neurosci. 12, 1285–1292 (2009).

  32. 32

    Hatton, G. I. Function-related plasticity in hypothalamus. Annu. Rev. Neurosci. 20, 375–397 (1997).

  33. 33

    Piet, R., Poulain, D. A. & Oliet, S. H. Modulation of synaptic transmission by astrocytes in the rat supraoptic nucleus. J. Physiol. (Paris) 96, 231–236 (2002).

  34. 34

    Fox, M. A. & Umemori, H. Seeking long-term relationship: axon and target communicate to organize synaptic differentiation. J. Neurochem. 97, 1215–1231 (2006).

  35. 35

    Fields, R. D. Myelination: an overlooked mechanism of synaptic plasticity? Neuroscientist 11, 528–531 (2005).

  36. 36

    Muller, C. M. & Best, J. Ocular dominance plasticity in adult cat visual cortex after transplantation of cultured astrocytes. Nature 342, 427–430 (1989).

  37. 37

    Meyer-Franke, A., Kaplan, M. R., Pfrieger, F. W. & Barres, B. A. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 15, 805–819 (1995).

  38. 38

    Pfrieger, F. W. & Barres, B. A. Synaptic efficacy enhanced by glial cells in vitro . Science 277, 1684–1687 (1997).

  39. 39

    Ullian, E. M., Sapperstein, S. K., Christopherson, K. S. & Barres, B. A. Control of synapse number by glia. Science 291, 657–661 (2001). References 38 and 39 show that synapse formation and function are powerfully affected by astrocytes in culture. This is the first report that these processes are not only controlled by neuronal mechanisms but can also be directed by glia.

  40. 40

    Wu, H. et al. Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines. Proc. Natl Acad. Sci. USA 104, 13821–13826 (2007).

  41. 41

    Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005). Following on from the work by Ullian and colleagues39, this paper identifies the extracellular matrix proteins TSPs as the synaptogenic factors that are released by astrocytes.

  42. 42

    Eroglu, C. et al. Gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139, 380–392 (2009). In this study, the receptor for TSPs that is involved in synapse formation was identified to be the Ca2+ channel subunit α 2 δ-1, which is also the receptor for the commonly prescribed pain medication gabapentin.

  43. 43

    Rohrbough, J., Grotewiel, M. S., Davis, R. L. & Broadie, K. Integrin-mediated regulation of synaptic morphology, transmission, and plasticity. J. Neurosci. 20, 6868–6878 (2000).

  44. 44

    Shi, Y. & Ethell, I. M. Integrins control dendritic spine plasticity in hippocampal neurons through NMDA receptor and Ca2+/calmodulin-dependent protein kinase II-mediated actin reorganization. J. Neurosci. 26, 1813–1822 (2006).

  45. 45

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

  46. 46

    Taylor, C. P. Mechanisms of analgesia by gabapentin and pregabalin: calcium channel α2-δ [Cavα2-δ] ligands. Pain 142, 13–16 (2009).

  47. 47

    Mauch, D. H. et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 294, 1354–1357 (2001).

  48. 48

    Goritz, C., Mauch, D. H. & Pfrieger, F. W. Multiple mechanisms mediate cholesterol-induced synaptogenesis in a CNS neuron. Mol. Cell. Neurosci. 29, 190–201 (2005).

  49. 49

    Elmariah, S. B., Hughes, E. G., Oh, E. J. & Balice-Gordon, R. J. Neurotrophin signaling among neurons and glia during formation of tripartite synapses. Neuron Glia Biol. 1, 1–11 (2005).

  50. 50

    Hughes, E. G., Elmariah, S. B. & Balice-Gordon, R. J. Astrocyte secreted proteins selectively increase hippocampal GABAergic axon length, branching, and synaptogenesis. Mol. Cell. Neurosci. 43, 136–145 (2009).

  51. 51

    Feng, Z. & Ko, C. P. Schwann cells promote synaptogenesis at the neuromuscular junction via transforming growth factor-β1. J. Neurosci. 28, 9599–9609 (2008).

  52. 52

    Cao, G. & Ko, C. P. Schwann cell-derived factors modulate synaptic activities at developing neuromuscular synapses. J. Neurosci. 27, 6712–6722 (2007).

  53. 53

    Arber, S. & Caroni, P. Thrombospondin-4, an extracellular matrix protein expressed in the developing and adult nervous system, promotes neurite outgrowth. J. Cell Biol. 131, 1083–1094 (1995).

  54. 54

    Arikkath, J. & Campbell, K. P. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr. Opin. Neurobiol. 13, 298–307 (2003).

  55. 55

    Barker, A. J., Koch, S. M., Reed, J., Barres, B. A. & Ullian, E. M. Developmental control of synaptic receptivity. J. Neurosci. 28, 8150–8160 (2008).

  56. 56

    Hama, H., Hara, C., Yamaguchi, K. & Miyawaki, A. PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes. Neuron 41, 405–415 (2004).

  57. 57

    Taniguchi, H. et al. Silencing of neuroligin function by postsynaptic neurexins. J. Neurosci. 27, 2815–2824 (2007).

  58. 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).

  59. 59

    Garrett, A. M. & Weiner, J. A. Control of CNS synapse development by γ-protocadherin-mediated astrocyte–neuron contact. J. Neurosci. 29, 11723–11731 (2009).

  60. 60

    Colon-Ramos, D. A., Margeta, M. A. & Shen, K. Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans . Science 318, 103–106 (2007).

  61. 61

    Bacaj, T., Tevlin, M., Lu, Y. & Shaham, S. Glia are essential for sensory organ function in C. elegans . Science 322, 744–747 (2008).

  62. 62

    Kurshan, P. T., Oztan, A. & Schwarz, T. L. Presynaptic α2δ-3 is required for synaptic morphogenesis independent of its Ca2+-channel functions. Nature Neurosci. 12, 1415–1423 (2009).

  63. 63

    Caceres, M., Suwyn, C., Maddox, M., Thomas, J. W. & Preuss, T. M. Increased cortical expression of two synaptogenic thrombospondins in human brain evolution. Cereb. Cortex 17, 2312–2321 (2007).

  64. 64

    Cummings, J. A., Mulkey, R. M., Nicoll, R. A. & Malenka, R. C. Ca2+ signaling requirements for long-term depression in the hippocampus. Neuron 16, 825–833 (1996).

  65. 65

    Selig, D. K., Hjelmstad, G. O., Herron, C., Nicoll, R. A. & Malenka, R. C. Independent mechanisms for long-term depression of AMPA and NMDA responses. Neuron 15, 417–426 (1995).

  66. 66

    Miller, R. F. D-Serine as a glial modulator of nerve cells. Glia 47, 275–283 (2004).

  67. 67

    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).

  68. 68

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

  69. 69

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

  70. 70

    Stellwagen, D. & Malenka, R. C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059 (2006).

  71. 71

    Buckby, L. E., Jensen, T. P., Smith, P. J. & Empson, R. M. Network stability through homeostatic scaling of excitatory and inhibitory synapses following inactivity in CA3 of rat organotypic hippocampal slice cultures. Mol. Cell. Neurosci. 31, 805–816 (2006).

  72. 72

    Freeman, M. R. Sculpting the nervous system: glial control of neuronal development. Curr. Opin. Neurobiol. 16, 119–125 (2006).

  73. 73

    Awasaki, T. & Ito, K. Engulfing action of glial cells is required for programmed axon pruning during Drosophila metamorphosis. Curr. Biol. 14, 668–677 (2004).

  74. 74

    Watts, R. J., Schuldiner, O., Perrino, J., Larsen, C. & Luo, L. Glia engulf degenerating axons during developmental axon pruning. Curr. Biol. 14, 678–684 (2004). References 73 and 74 are the first reports that the pruning of axons during Drosophila metamorphosis is mediated by their active engulfment by glia.

  75. 75

    MacDonald, J. M. et al. The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons. Neuron 50, 869–881 (2006).

  76. 76

    Awasaki, T. et al. Essential role of the apoptotic cell engulfment genes draper and ced-6 in programmed axon pruning during Drosophila metamorphosis. Neuron 50, 855–867 (2006).

  77. 77

    Kurant, E., Axelrod, S., Leaman, D. & Gaul, U. Six-microns-under acts upstream of Draper in the glial phagocytosis of apoptotic neurons. Cell 133, 498–509 (2008).

  78. 78

    Ziegenfuss, J. S. et al. Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling. Nature 453, 935–939 (2008).

  79. 79

    Bishop, D. L., Misgeld, T., Walsh, M. K., Gan, W. B. & Lichtman, J. W. Axon branch removal at developing synapses by axosome shedding. Neuron 44, 651–661 (2004).

  80. 80

    Song, J. W. et al. Lysosomal activity associated with developmental axon pruning. J. Neurosci. 28, 8993–9001 (2008).

  81. 81

    Fuentes-Medel, Y. et al. Glia and muscle sculpt neuromuscular arbors by engulfing destabilized synaptic boutons and shed presynaptic debris. PLoS Biol. 7, e1000184 (2009).

  82. 82

    Wu, H. H. et al. Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nature Neurosci. 12, 1534–1541 (2009).

  83. 83

    Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007). This study describes an unexpected role for the complement cascade in the elimination of synapses during development and provides evidence that the expression of complement proteins is upregulated and their synaptic localization increases during the early stages of glaucoma.

  84. 84

    Chu, Y. et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc. Natl Acad. Sci. USA 107, 7975–7980 (2010).

  85. 85

    Alexander, J. J., Anderson, A. J., Barnum, S. R., Stevens, B. & Tenner, A. J. The complement cascade: Yin–Yang in neuroinflammation — neuro-protection and -degeneration. J. Neurochem. 107, 1169–1187 (2008).

  86. 86

    Cullheim, S. & Thams, S. The microglial networks of the brain and their role in neuronal network plasticity after lesion. Brain Res. Rev. 55, 89–96 (2007).

  87. 87

    Urade, Y., Oberdick, J., Molinar-Rode, R. & Morgan, J. I. Precerebellin is a cerebellum-specific protein with similarity to the globular domain of complement C1q B chain. Proc. Natl Acad. Sci. USA 88, 1069–1073 (1991).

  88. 88

    Iijima, T., Miura, E., Watanabe, M. & Yuzaki, M. Distinct expression of C1q-like family mRNAs in mouse brain and biochemical characterization of their encoded proteins. Eur. J. Neurosci. 31, 1606–1615 (2010).

  89. 89

    Matsuda, K. et al. Cbln1 is a ligand for an orphan glutamate receptor δ2, a bidirectional synapse organizer. Science 328, 363–368 (2010).

  90. 90

    Koch, S. M. & Ullian, E. M. Neuronal pentraxins mediate silent synapse conversion in the developing visual system. J. Neurosci. 30, 5404–5414 (2010).

  91. 91

    Johnson, E. C. & Morrison, J. C. Friend or foe? Resolving the impact of glial responses in glaucoma. J. Glaucoma 18, 341–353 (2009).

  92. 92

    Lin, T. N. et al. Differential regulation of thrombospondin-1 and thrombospondin-2 after focal cerebral ischemia/reperfusion. Stroke 34, 177–186 (2003).

  93. 93

    Tran, M. D. & Neary, J. T. Purinergic signaling induces thrombospondin-1 expression in astrocytes. Proc. Natl Acad. Sci. USA 103, 9321–9326 (2006).

  94. 94

    Liauw, J. et al. Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J. Cereb. Blood Flow Metab. 28, 1722–1732 (2008).

  95. 95

    Li, C. Y., Song, Y. H., Higuera, E. S. & Luo, Z. D. Spinal dorsal horn calcium channel α2δ-1 subunit upregulation contributes to peripheral nerve injury-induced tactile allodynia. J. Neurosci. 24, 8494–8499 (2004).

  96. 96

    Valder, C. R., Liu, J. J., Song, Y. H. & Luo, Z. D. Coupling gene chip analyses and rat genetic variances in identifying potential target genes that may contribute to neuropathic allodynia development. J. Neurochem. 87, 560–573 (2003).

  97. 97

    Oliveira, A. L. et al. A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc. Natl Acad. Sci. USA 101, 17843–17848 (2004).

Download references


We acknowledge all of our colleagues whose important work was not directly cited here because of space limitations. This work is referenced in the review articles cited here. C.E. is supported by the Alfred P. Sloan Foundation and a Klingenstein Fellowship Award in the Neurosciences, from the Esther A. & Joseph Klingenstein Fund.

Author information

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Eroglu, C., Barres, B. Regulation of synaptic connectivity by glia. Nature 468, 223–231 (2010) doi:10.1038/nature09612

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.