Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Prostaglandins stimulate calcium-dependent glutamate release in astrocytes

Abstract

Astrocytes in the brain form an intimately associated network with neurons. They respond to neuronal activity and synaptically released glutamate by raising intracellular calcium concentration ([Ca2+]i)1,2 which could represent the start of back-signalling to neurons3,4,5. Here we show that coactivation of the AMPA/kainate and metabotropic glutamate receptors (mGluRs) on astrocytes stimulates these cells to release glutamate through a Ca2+-dependent process mediated by prostaglandins. Pharmacological inhibition of prostaglandin synthesis prevents glutamate release, whereas application of prostaglandins (in particular PGE2) mimics and occludes the releasing action of GluR agonists. PGE2 promotes Ca2+-dependent glutamate release from cultured astrocytes and also from acute brain slices under conditions that suppress neuronal exocytotic release. When applied to the CA1 hippocampal region, PGE2 induces increases in [Ca2+]i both in astrocytes and in neurons. The [Ca2+]i increase in neurons is mediated by glutamate released from astrocytes, because it is abolished by GluR antagonists. Our results reveal a new pathway of regulated transmitter release from astrocytes and outline the existence of an integrated glutamatergic cross-talk between neurons and astrocytes in situ that may play critical roles in synaptic plasticity and in neurotoxicity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Ca2+-dependent glutamate release from astrocytes in response to joint stimulation of AMPARs and mGluRs.
Figure 2: Activation of the arachidonate cascade and involvement of prostaglandins in the Ca2+-dependent release of glutamate from a.
Figure 3: AMPA + t-ACPD and PGE2 stimulate glutamate release from hippocampal slices with blocked neuronal exocytosis.
Figure 4: Effects of PGE2 on the [Ca2+]i of Indo-1-loaded hippocampal cells.

Similar content being viewed by others

References

  1. Dani, J. W., Chernjavski, A. & Smith, S. J. Neuronal activity triggers calcium waves in hippocampal astrocyte networks. Neuron 8, 429–440 (1992).

    Article  CAS  Google Scholar 

  2. 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 

  3. Nedergaard, M. Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science 263, 1768–1771 (1994).

    Article  ADS  CAS  Google Scholar 

  4. Parpura, V. et al. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994).

    Article  ADS  CAS  Google Scholar 

  5. Hassinger, T. D. et al. Evidence for glutamate-mediated activation of hippocampal neurons by glial calcium waves. J. Neurobiol. 28, 159–170 (1995).

    Article  CAS  Google Scholar 

  6. Nicholls, D. G., Sihra, T. S. & Sanchez-Prieto, J. Calcium-dependent and -independent release of glutamate from synaptosomes monitored by continuous fluorometry. J. Neurochem. 49, 50–57 (1987).

    Article  CAS  Google Scholar 

  7. Steinhäuser, C. & Gallo, V. News on glutamate receptors in glial cells. Trends Neurosci. 19, 339–345 (1996).

    Article  Google Scholar 

  8. Szatkowski, M., Barbour, B. & Attwell, D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 348, 443–447 (1990).

    Article  ADS  CAS  Google Scholar 

  9. Kimelberg, H. K., Goderie, S. K., Higman, S., Pang, S. & Waniewski, R. A. Swelling-induced release of glutamate, aspartate and taurine from astrocyte cultures. J. Neurosci. 10, 1583–1591 (1990).

    Article  CAS  Google Scholar 

  10. Vesce, S., Bezzi, P., Rossi, D., Meldolesi, J. & Volterra, A. HIV-1 gp120 glycoprotein affects the astrocyte control of extracellular glutamate by both inhibiting the uptake and stimulating the release of the amino acid. FEBS Lett. 411, 107–109 (1997).

    Article  CAS  Google Scholar 

  11. Volterra, A. et al. The competitive transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate triggers excitotoxicity in rat cortical neuron-astrocyte co-coltures via glutamate release rather than uptake inhibition. Eur. J. Neurosci. 8, 2019–2028 (1996).

    Article  CAS  Google Scholar 

  12. Eriksson, P. S., Nilsson, M., Wågberg, M., Rönnbäck, L. & Hansson, E. Volume regulation of single astroglial cells in primary culture. Neurosci. Lett. 143, 195–199 (1992).

    Article  CAS  Google Scholar 

  13. Jeftinija, S. D., Jeftinija, K. V. & Stefanovic, G. Cultured astrocytes express proteins involved in vesicular glutamate release. Brain Res. 750, 41–47 (1997).

    Article  CAS  Google Scholar 

  14. Schiavo, G. et al. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 359, 832–835 (1992).

    Article  ADS  CAS  Google Scholar 

  15. Jeftinija, S. D., Jeftinija, K. V., Stefanovic, G. & Liu, F. Neuroligand-evoked calcium-dependent release of excitatory amino acids from cultured astrocytes. J. Neurochem. 66, 674–684 (1996).

    Google Scholar 

  16. Dumuis, A., Pin, J. P., Oomagari, K., Sebben, M. & Bockaert, J. Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature 347, 182–184 (1990).

    Article  ADS  CAS  Google Scholar 

  17. Piomelli, D. Eicosanoids in synaptic transmission. Crit. Rev. Neurobiol. 8, 65–83 (1994).

    CAS  PubMed  Google Scholar 

  18. Oomagari, K., Buisson, B., Dumuis, A., Bockaert, J. & Pin, J.-P. Effect of glutamate and ionomycin on the release of arachidonic acid, prostaglandins and HETEs from cultured neurons and astrocytes. Eur. J. Neurosci. 3, 928–939 (1991).

    Article  Google Scholar 

  19. Grynkiewicz, G., Poenie, M. & Tsien, R. Y. Anew generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260, 3440–3450 (1985).

    CAS  PubMed  Google Scholar 

  20. Calabresi, P., Benedetti, M., Mercuri, N. B. & Bernardi, G. Selective depression of synaptic transmission by tetanus toxin: a comparative study on hippocampal and neostriatal slices. Neuroscience 30, 663–670 (1989).

    Article  CAS  Google Scholar 

  21. Mennerick, S., Benz, A. & Zorumski, C. F. Components of glial responses to exogenous and synaptic glutamate in rat hippocampal microcultures. J. Neurosci. 16, 55–64 (1996).

    Article  CAS  Google Scholar 

  22. Pasti, L., Volterra, A., Pozzan, T. & Carmignoto, G. Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J. Neurosci. 17, 7817–7830 (1997).

    Article  CAS  Google Scholar 

  23. Baran, H., Heldt, R. & Hertting, G. Increased prostaglandin formation in rat brain following systemic application of kainic acid. Brain Res. 404, 107–112 (1987).

    Article  CAS  Google Scholar 

  24. Malmberg, A. B. & Yaksh, T. L. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science 257, 1276–1279 (1992).

    Article  ADS  CAS  Google Scholar 

  25. Collaco-Moraes, Y., Asprey, B., Harrison, M. & de Belleroche, J. Cyclo-oxygenase-2 messenger RNA induction in focal cerebral ischemia. J. Cereb. Blood Flow Metab. 16, 1366–1372 (1996).

    Article  CAS  Google Scholar 

  26. O'Banion, M. K., Miller, J. C., Chang, J. W., Kaplan, M. D. & Coleman, P. D. Interleukin-1 β induces prostaglandin G/H synthase 2 (cyclooxygenase-2) in primary murine astrocyte cultures. J. Neurochem. 66, 2532–2540 (1996).

    Article  CAS  Google Scholar 

  27. Carmignoto, G. & Vicini, S. Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258, 1007–1011 (1992).

    Article  ADS  CAS  Google Scholar 

  28. Stella, N., Tencé, M., Glowinski, J. & Prémont, J. Glutamate-evoked release of arachidonic acid from mouse brain astrocytes. J. Neurosci. 14, 568–575 (1994).

    Article  CAS  Google Scholar 

  29. Edwards, F. A., Konnerth, A., Sakmann, B. & Takahashi, T. Athin slice preparation for patch clamp recordings from synaptically connected neurons of the mammalian central nervous system. Pflügers Arch. 414, 600–612 (1989).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Montecucco for the generous supply of purified tetanus neurotoxin; J.Meldolesi and R. Paoletti for critical reading of the manuscript and advice; S. Nicosia for suggestions and use of facilities; and B. Viviani, M. R. Accomazzo and P. Ciceri for experimental help. This work was supported by grants for the European Community, ‘Biomed 2 Contract BMH4-CT95-0571’ and Telethon-Italy to A.V., and from Human Frontier Science Program RG520/95 and Telethon-Italy to T.P.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrea Volterra.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bezzi, P., Carmignoto, G., Pasti, L. et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, 281–285 (1998). https://doi.org/10.1038/34651

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/34651

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing