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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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.
The authors declare no competing financial interests.
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