The tripartite synapse

  • Michael M. Halassa
  • Philip G. Haydon

The study of the astrocyte was hampered during the 1900s by the lack of experimental techniques to permit experimental stimulation and recording of the function of the astrocyte. Even in the early 1900s it was appreciated that electrical signals were the mechanism of conduction of neuronal signals (Adrian, 1912). Since astrocytes exhibit a large negative resting potential (Butt and Kalsi, 2006) their functional activity was mute to the electrophysiological techniques used to study nervous system function.

Despite the poor experimental tractability of astrocytes, several pioneering studies did, however, provide important insights into the functional roles for these glia in brain function. Microscopy, immunocytochemistry, and biochemistry were used to identify glycogen storage granules (Magistretti, 2006; Tsacopoulos and Magistretti, 1996), and the presence of glutamate transporters (Anderson and Swanson, 2000) in astrocytic membranes. These observations provided a basis for the...


Synaptic Transmission P2Y1 Receptor Excitatory Synaptic Transmission Schaffer Collateral Astrocytic Process 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Adenosine 5′-triphosphate




Supraoptic nucleus


  1. Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: Review of properties, regulation, and physiological functions. Glia 32:1–14.PubMedCrossRefGoogle Scholar
  2. Adrian ED (1912) On the conduction of subnormal disturbances in normal nerve. J Physiol 45:389–412.PubMedGoogle Scholar
  3. Barbe MT, Monyer H, Bruzzone R (2006) Cell–Cell Communication Beyond Connexins: The Pannexin Channels. Physiology 21:103–114.PubMedCrossRefGoogle Scholar
  4. Bezzi P, Gundersen V, Galbete JL, Seifert G, Steinhauser C, Pilati E, Volterra A (2004) Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 7:613–620.PubMedCrossRefGoogle Scholar
  5. Bowser DN, Khakh BS (2004) ATP excites interneurons and astrocytes to increase synaptic inhibition in neuronal networks. J Neurosci 24:8606–8620.PubMedCrossRefGoogle Scholar
  6. Butt AM, Kalsi A (2006) Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions. J Cell Mol Med 10:33–44.PubMedCrossRefGoogle Scholar
  7. Cornell Bell AH, Finkbeiner SM, Cooper MS, Smith SJ (1990) Glutamate induces calcium waves in cultured astrocytes: long- range glial signaling. Science 247:470–473.PubMedCrossRefGoogle Scholar
  8. Ding S, Fellin T, Zhu Y, Lee SY, Auberson YP, Meaney DF, Coulter DA, Carmignoto G, Haydon PG (2007) Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus. J Neurosci 27:10674–10684.PubMedCrossRefGoogle Scholar
  9. Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G (2004) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43:729–743.PubMedCrossRefGoogle Scholar
  10. Fellin T, Pozzan T, Carmignoto G (2006) Purinergic receptors mediate two distinct glutamate release pathways in hippocampal astrocytes. J Biol Chem 281:4274–4284.PubMedCrossRefGoogle Scholar
  11. Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19:520–528.PubMedGoogle Scholar
  12. Hertz L, Zielke HR (2004) Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci 27:735–743.PubMedCrossRefGoogle Scholar
  13. Jourdain P, Bergersen LH, Bhaukaurally K, Bezzi P, Santello M, Domercq M, Matute C, Tonello F, Gundersen V, Volterra A (2007) Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci 10:331–339.PubMedCrossRefGoogle Scholar
  14. Magistretti PJ (2006) Neuron-glia metabolic coupling and plasticity. J Exp Biol 209:2304–2311.PubMedCrossRefGoogle Scholar
  15. Montana V, Ni Y, Sunjara V, Hua X, Parpura V (2004) Vesicular glutamate transporter-dependent glutamate release from astrocytes. J Neurosci 24:2633–2642.PubMedCrossRefGoogle Scholar
  16. Mothet JP, Parent AT, Wolosker H, Brady RO, Jr., Linden DJ, Ferris CD, Rogawski MA, Snyder SH (2000) D-Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A 97:4926–4931.PubMedCrossRefGoogle Scholar
  17. Mothet JP, Pollegioni L, Ouanounou G, Martineau M, Fossier P, Baux G (2005) Glutamate receptor activation triggers a calcium-dependent and SNARE protein-dependent release of the gliotransmitter D-serine. Proc Natl Acad Sci U S A 102:5606–5611.PubMedCrossRefGoogle Scholar
  18. Nedergaard M (1994) Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263:1768–1771.PubMedCrossRefGoogle Scholar
  19. Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L, Poulain DA, Oliet SH (2006) Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125:775–784.PubMedCrossRefGoogle Scholar
  20. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747.PubMedCrossRefGoogle Scholar
  21. Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG (2005) Astrocytic purinergic signaling coordinates synaptic networks. Science 310:113–116.PubMedCrossRefGoogle Scholar
  22. Pasti L, Volterra A, Pozzan T, Carmignoto G (1997) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J Neurosci 17:7817–7830.PubMedGoogle Scholar
  23. Scammell TE, Arrigoni E, Thompson MA, Ronan PJ, Saper CB, Greene RW (2003) Focal deletion of the adenosine A1 receptor in adult mice using an adeno-associated viral vector. J Neurosci 23:5762–5770.PubMedGoogle Scholar
  24. Schell MJ, Molliver ME, Snyder SH (1995) D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci U S A 92:3948–3952.PubMedCrossRefGoogle Scholar
  25. Takano T, Kang J, Jaiswal JK, Simon SM, Lin JH, Yu Y, Li Y, Yang J, Dienel G, Zielke HR, Nedergaard M (2005) Receptor-mediated glutamate release from volume sensitive channels in astrocytes. Proc Natl Acad Sci U S A 102:16466–16471.PubMedCrossRefGoogle Scholar
  26. Tsacopoulos M, Magistretti PJ (1996) Metabolic coupling between glia and neurons. J Neurosci 16:877–885.PubMedGoogle Scholar
  27. Wang X, Lou N, Xu Q, Tian GF, Peng WG, Han X, Kang J, Takano T, Nedergaard M (2006) Astrocytic Ca(2+) signaling evoked by sensory stimulation in vivo. Nat Neurosci 9:816–823.PubMedCrossRefGoogle Scholar
  28. Wolosker H, Sheth KN, Takahashi M, Mothet JP, Brady RO, Jr., Ferris CD, Snyder SH (1999) Purification of serine racemase: biosynthesis of the neuromodulator D-serine. Proc Natl Acad Sci U S A 96:721–725.PubMedCrossRefGoogle Scholar
  29. Ye ZC, Wyeth MS, Baltan-Tekkok S, Ransom BR (2003) Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci 23:3588–3596.PubMedGoogle Scholar
  30. Zhang Q, Fukuda M, Van Bockstaele E, Pascual O, Haydon PG (2004a) Synaptotagmin IV regulates glial glutamate release. Proc Natl Acad Sci U S A 101:9441–9446.CrossRefGoogle Scholar
  31. Zhang Q, Pangrsic T, Kreft M, Krzan M, Li N, Sul JY, Halassa M, Van Bockstaele E, Zorec R, Haydon PG (2004b) Fusion-related release of glutamate from astrocytes. J Biol Chem 279:12724–12733.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Michael M. Halassa
    • 1
  • Philip G. Haydon
    • 1
  1. 1.University of Pennsylvania School of MedicineDepartment of NeuroscienceUSA

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