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Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy

Nature Neuroscience volume 8, pages 1078–1086 (2005)Cite this article

Abstract

Glial cells actively participate in synaptic transmission. They clear molecules from the synaptic cleft, receive signals from neurons and, in turn, release molecules that can modulate signaling between neuronal elements. Whether glial-derived transmitters can contribute to enduring changes in postsynaptic efficacy, however, remains to be established. In rat hypothalamic paraventricular nucleus, we demonstrate an increase in the amplitude of miniature excitatory postsynaptic currents in response to norepinephrine that requires the release of ATP from glial cells. The increase in quantal efficacy, which likely results from an insertion of AMPA receptors, is secondary to the activation of P2X7 receptors, an increase in postsynaptic calcium and the activation of phosphatidylinositol 3-kinase. The gliotransmitter ATP, therefore, contributes directly to the regulation of postsynaptic efficacy at glutamatergic synapses in the CNS.

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Figure 1: Norepinephrine induces an enduring increase in mEPSC amplitude that is accompanied by an increase in postsynaptic efficacy.
Figure 2: The enduring increase in mEPSC amplitude is not associated with an increase in AMPA channel conductance.
Figure 3: The enduring increase in mEPSC amplitude requires SNARE-dependent exocytosis, an increase in postsynaptic calcium and activation of PI3K.
Figure 4: The enduring increase in mEPSC amplitude does not involve postsynaptic α1-adrenoceptors or glutamate signaling.
Figure 5: Activation of P2X7 receptors is necessary and sufficient for the expression of the enduring increase in mEPSC amplitude.
Figure 6: Norepinephrine targets glial cells to release ATP.
Figure 7: Glial cells are necessary for the enduring increase in mEPSC amplitude triggered by α1-adrenoceptor activation.
Figure 8: A general rise in calcium in glial cells does not mimic the enduring increase in mEPSC amplitude observed in response to norepinephrine.

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Acknowledgements

We thank C. Sank for technical assistance and for conducting the immunohistochemistry experiments. We are also grateful to Q. Pittman for assistance with the dehydration protocol and for comments on an earlier version of the manuscript and to S. Oliet and B. MacVicar for helpful discussions. This work was supported by operating grants to J.S.B. from the Canadian Institutes of Health Research (CIHR) and T.E.F. from the Heart and Stroke Foundation of Saskatchewan. G.R.J.G. is supported by a studentship from the Natural Sciences and Engineering Research Council. J.S.B. is a CIHR New Investigator and an Alberta Heritage Foundation for Medical Research Scholar. T.E.F. is a CIHR/Regional Partnership Program New Investigator.

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  1. Hotchkiss Brain Institute and the Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive NW, Calgary, T2N 4N1, Alberta, Canada

    Grant R J Gordon, Dinara V Baimoukhametova, Sarah A Hewitt & Jaideep S Bains

  2. Department of Physiology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, S7N 5E5, Saskatchewan, Canada

    W R A Kosala J S Rajapaksha & Thomas E Fisher

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Correspondence to Jaideep S Bains.

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Gordon, G., Baimoukhametova, D., Hewitt, S. et al. Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy. Nat Neurosci 8, 1078–1086 (2005). https://doi.org/10.1038/nn1498

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