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Long-term potentiation depends on release of d-serine from astrocytes


Long-term potentiation (LTP) of synaptic transmission provides an experimental model for studying mechanisms of memory1. The classical form of LTP relies on N-methyl-d-aspartate receptors (NMDARs), and it has been shown that astroglia can regulate their activation through Ca2+-dependent release of the NMDAR co-agonist d-serine2,3,4. Release of d-serine from glia enables LTP in cultures5 and explains a correlation between glial coverage of synapses and LTP in the supraoptic nucleus4. However, increases in Ca2+ concentration in astroglia can also release other signalling molecules, most prominently glutamate6,7,8, ATP9 and tumour necrosis factor-α10,11, whereas neurons themselves can synthesize and supply d-serine12,13. Furthermore, loading an astrocyte with exogenous Ca2+ buffers does not suppress LTP in hippocampal area CA1 (refs 14–16), and the physiological relevance of experiments in cultures or strong exogenous stimuli applied to astrocytes has been questioned17,18. The involvement of glia in LTP induction therefore remains controversial. Here we show that clamping internal Ca2+ in individual CA1 astrocytes blocks LTP induction at nearby excitatory synapses by decreasing the occupancy of the NMDAR co-agonist sites. This LTP blockade can be reversed by exogenous d-serine or glycine, whereas depletion of d-serine or disruption of exocytosis in an individual astrocyte blocks local LTP. We therefore demonstrate that Ca2+-dependent release of d-serine from an astrocyte controls NMDAR-dependent plasticity in many thousands of excitatory synapses nearby.

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Figure 1: Clamping astrocytic Ca 2+ blocks LTP at nearby synapses in a d -serine-dependent manner.
Figure 2: Activation of the NMDAR co-agonist site is astrocyte-dependent and use-dependent.
Figure 3: LTP expression depends on the occupancy of the NMDAR co-agonist sites controlled by d -serine synthesis in a nearby astrocyte.
Figure 4: Individual astrocytes influence LTP induction mainly at nearby synapses.


  1. Bliss, T. V. P. & Collingridge, G. L. A synaptic model of memory—long-term potentiation in the hippocampus. Nature 361, 31–39 (1993)

    Article  ADS  CAS  Google Scholar 

  2. Schell, M. J., Molliver, M. E. & Snyder, S. H. d-Serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc. Natl Acad. Sci. USA 92, 3948–3952 (1995)

    Article  ADS  CAS  Google Scholar 

  3. 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  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  12. 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, 14151–14162 (2006)

    Article  CAS  Google Scholar 

  13. Miya, K. et al. Serine racemase is predominantly localized in neurons in mouse brain. J. Comp. Neurol. 510, 641–654 (2008)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Luscher, C., Malenka, R. C. & Nicoll, R. A. Monitoring glutamate release during LTP with glial transporter currents. Neuron 21, 435–441 (1998)

    Article  CAS  Google Scholar 

  16. Ge, W. P. & Duan, S. M. Persistent enhancement of neuron–glia signaling mediated by increased extracellular K+ accompanying long-term synaptic potentiation. J. Neurophysiol. 97, 2564–2569 (2007)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Baker, P. F., Knight, D. E. & Umbach, J. A. Calcium clamp of the intracellular environment. Cell Calcium 6, 5–14 (1985)

    Article  CAS  Google Scholar 

  20. Duffy, S., Labrie, V. & Roder, J. C. d-Serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. Neuropsychopharmacology 33, 1004–1018 (2008)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  22. Li, Y., Krupa, B., Kang, J. S., Bolshakov, V. Y. & Liu, G. S. Glycine site of NMDA receptor serves as a spatiotemporal detector of synaptic activity patterns. J. Neurophysiol. 102, 578–589 (2009)

    Article  CAS  Google Scholar 

  23. Fellin, T. et al. Endogenous nonneuronal modulators of synaptic transmission control cortical slow oscillations in vivo . Proc. Natl Acad. Sci. USA 106, 15037–15042 (2009)

    Article  ADS  CAS  Google Scholar 

  24. 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  Google Scholar 

  25. 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)

    Article  CAS  Google Scholar 

  26. Strisovsky, K., Jiraskova, J., Mikulova, A., Rulisek, L. & Konvalinka, J. Dual substrate and reaction specificity in mouse serine racemase: Identification of high-affinity dicarboxylate substrate and inhibitors and analysis of the β-eliminase activity. Biochemistry 44, 13091–13100 (2005)

    Article  CAS  Google Scholar 

  27. 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)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  29. 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  Google Scholar 

  30. Rusakov, D. A. & Kullmann, D. M. Extrasynaptic glutamate diffusion in the hippocampus: ultrastructural constraints, uptake, and receptor activation. J. Neurosci. 18, 3158–3170 (1998)

    Article  CAS  Google Scholar 

  31. Bergles, D. E. & Jahr, C. E. Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. J. Neurosci. 18, 7709–7716 (1998)

    Article  CAS  Google Scholar 

  32. Volterra, A. & Meldolesi, J. Astrocytes, from brain glue to communication elements: the revolution continues. Nature Rev. Neurosci. 6, 626–640 (2005)

    Article  CAS  Google Scholar 

  33. Xu, T., Binz, T., Niemann, H. & Neher, E. Multiple kinetic components of exocytosis distinguished by neurotoxin sensitivity. Nature Neurosci. 1, 192–200 (1998)

    Article  CAS  Google Scholar 

  34. Szerb, J. C. & Issekutz, B. Increase in the stimulation-induced overflow of glutamate by fluoroacetate, a selective inhibitor of the glial tricarboxylic cycle. Brain Res. 410, 116–120 (1987)

    Article  CAS  Google Scholar 

  35. Rusakov, D. A. & Fine, A. Extracellular Ca2+ depletion contributes to fast activity-dependent modulation of synaptic transmission in the brain. Neuron 37, 287–297 (2003)

    Article  CAS  Google Scholar 

  36. Oertner, T. G., Sabatini, B. L., Nimchinsky, E. A. & Svoboda, K. Facilitation at single synapses probed with optical quantal analysis. Nature Neurosci. 5, 657–664 (2002)

    Article  CAS  Google Scholar 

  37. Scott, R., Ruiz, A., Henneberger, C., Kullmann, D. M. & Rusakov, D. A. Analog modulation of mossy fiber transmission is uncoupled from changes in presynaptic Ca2+ . J. Neurosci. 28, 7765–7773 (2008)

    Article  CAS  Google Scholar 

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We thank D. Kullmann, J. Diamond, T. Bliss and K. Volynski for comments and suggestions. This work was supported by the Human Frontier Science Programme (D.A.R. and S.H.R.O.), the Wellcome Trust (Senior Fellowship to D.A.R.), the Medical Research Council (UK), the European Union (Promemoria), INSERM, Université de Bordeaux, the Fondation pour la Recherche Médicale (Équipe FRM, to S.H.R.O.), National Alliance for Research on Schizophrenia and Depression (NARSAD; Independent Investigator, SHRO), Agence National de la Recherche, Fédération pour la Recherche sur le Cerveau, Conseil Régional d’Aquitaine and a studentship from the French Ministry of Research to T.P.

Author Contributions C.H. and T.P. performed experimental studies; C.H., T.P., S.H.R.O. and D.A.R. analysed the data and wrote the paper.

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Correspondence to Stéphane H. R. Oliet or Dmitri A. Rusakov.

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Henneberger, C., Papouin, T., Oliet, S. et al. Long-term potentiation depends on release of d-serine from astrocytes. Nature 463, 232–236 (2010).

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