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Glutamate exocytosis from astrocytes controls synaptic strength


The release of transmitters from glia influences synaptic functions. The modalities and physiological functions of glial release are poorly understood. Here we show that glutamate exocytosis from astrocytes of the rat hippocampal dentate molecular layer enhances synaptic strength at excitatory synapses between perforant path afferents and granule cells. The effect is mediated by ifenprodil-sensitive NMDA ionotropic glutamate receptors and involves an increase of transmitter release at the synapse. Correspondingly, we identify NMDA receptor 2B subunits on the extrasynaptic portion of excitatory nerve terminals. The receptor distribution is spatially related to glutamate-containing synaptic-like microvesicles in the apposed astrocytic processes. This glial regulatory pathway is endogenously activated by neuronal activity–dependent stimulation of purinergic P2Y1 receptors on the astrocytes. Thus, we provide the first combined functional and ultrastructural evidence for a physiological control of synaptic activity via exocytosis of glutamate from astrocytes.

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Figure 1: Astrocyte stimulation potentiates excitatory synaptic transmission in granule cells.
Figure 2: Blockade of exocytosis in astrocytes prevents the astrocyte-evoked enhancement of mEPSC frequency in granule cells.
Figure 3: NR2B-containing NMDARs mediate the enhancement of mEPSC frequency in granule cells.
Figure 4: NR2B in extrasynaptic terminal membranes is close to SLMVs in apposed astrocytic processes, and SLMVs are close to the astrocytic plasma membranes that face NR2B.
Figure 5: Neuronal activity-dependent [Ca2+]i elevation in molecular layer astrocytes: role of P2Y1Rs.
Figure 6: Astrocyte P2Y1R-dependent potentiation of excitatory transmission in granule cells via NR2B-containing NMDARs.

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We thank A. Pietropoli for initial electrophysiology experiments, T. Ivanova for testing the activity of TeNT in astrocytic membrane fractions, D. Attwell and J. Storm-Mathisen for critical comments to the present manuscript and D. Kullmann, D. Muller and S. Oliet for critical comments to previous versions, helpful discussions and suggestions. This work was supported by grants from the Swiss National Science Foundation (3100A0-100850) and Swiss State Secretariat for Education and Research (00.0553) to A.V. and from the Norwegian Research Council to L.H.B. and V.G.

Author information

Authors and Affiliations



P.J. conducted most of the electrophysiology experiments and analyses of the electrophysiology data. L.H.B. conducted the immunogold experiments and the analysis of the immunogold data. K.B. conducted the Ca2+ imaging experiments and some of the electrophysiology experiments. P.B. supervised the Ca2+ imaging experiments and the analysis of the Ca2+ imaging data. M.S. conducted part of the analyses of the electrophysiology data. M.D. and C.M. conducted the light and electron microscopy experiments concerning P2Y1R localization. F.T. prepared TeNTLC and TeNTLCE271A. V.G. supervised the immunogold experiments as well as the analysis of the immunogold data and participated in writing the manuscript. A.V. supervised the project and wrote the manuscript.

Corresponding authors

Correspondence to Vidar Gundersen or Andrea Volterra.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The protocol of depolarizing pulses applied to astrocytes does not modify their electrical membrane properties. (PDF 155 kb)

Supplementary Fig. 2

The effect induced by astrocyte stimulation on sEPSC activity in GCs is not reproduced by stimulation of the surrounding neuropil. (PDF 155 kb)

Supplementary Fig. 3

The ifenprodil-sensitive increase in mEPSC frequency in GCs induced by astrocyte stimulation or by direct NMDA application is not accompanied by a change in the amplitude of the miniature events. (PDF 61 kb)

Supplementary Fig. 4

Internal perfusion of MK-801 in GCs effectively blocks GC NMDA receptors, but does not modify the ifenprodil-sensitive NMDA effect on mEPSCs. (PDF 236 kb)

Supplementary Fig. 5

The distribution of NR2B immunogold particles across the extrasynaptic parts of the terminal's membrane where it faces astrocytes suggests that the receptor is inserted in the plasma membrane of the terminal. (PDF 48 kb)

Supplementary Fig. 6

BAPTA diffusion through the astrocytic syncytium. (PDF 106 kb)

Supplementary Table 1

Depolarizing pulses for stimulating astrocytes or neuropil. (PDF 28 kb)

Supplementary Table 2

Astrocyte stimulation induces preferentially mEPSC frequency increase, not SICs, in GCs. (PDF 21 kb)

Supplementary Data

Astrocyte [Ca2+]i elevations in response to depolarizing stimuli: involvement of Ca2+ release from the internal stores and independence on Ca2+ entry. (PDF 25 kb)

Supplementary Note

About the functional connectivity between ML astrocytes and GC synapses. (PDF 22 kb)

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

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