Contribution of Astrocyte Glutamate Release to Excitotoxicity

  • Daniela Rossi
  • Paola Bezzi
  • Maria Domercq
  • Liliana Brambilla
  • Jacopo Meldolesi
  • Andrea Volterra


Although glial cells have been traditionally viewed as supportive partners of neurons, recent studies demonstrated that astrocytes possess functional receptors and are able to release transmitters by regulated pathways. Astrocytes were found to react to synaptically released neurotransmitters by undergoing intracellular calcium elevation which subsequently triggers an exocytosis-like glial transmitter release. These findings led to a new concept of neuron-glia intercommunication where astrocytes play an unsuspected dynamic role by integrating neuronal inputs and modulating synaptic activity. The discovery that glial release of the excitatory amino acid glutamate is controlled by molecules linked to inflammatory functions, such as cytokines and prostaglandins, suggested that glia-to-neuron signalling may be implicated in physiological processes but also in pathological situations. Indeed, a local and parenchimal inflammatory reaction characterised by astroglia and microglia activation has been reported in several brain pathologies including prion diseases and various dementias like Alzheimer’s disease and the AIDS dementia complex. In agreement, stimulation of the calcium-dependent glial glutamate release process via activation of the chemokine receptor, CXCR4, by its natural ligand, SDF1α, is crucial for normal brain communication. However, the interaction of the same receptor with the HIV-1 coat protein gp120 in pathological conditions caused deregulation of the glutamate system and excitotoxic neuronal cell death. The findings herein reported suggest that a better comprehension of the glial-neuron glutamatergic interplay may provide information about nonnal brain functions and may highlight possible molecular targets for therapeutical interventions in pathology.


astrocytes glutamate release excitotoxicity glial signalling calcium 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bagetta, G., Corasaniti, M.T., Malorni, W., Rainaldi, G., Berliocchi, L., Finazzi-Agro, A. and Nistico, G. (1996) The HIV-1 gp120 causes ultrastructural changes typical of apoptosis in the rat cerebral cortex. Neuroreport, 7, 1722–1724.PubMedCrossRefGoogle Scholar
  2. Bezzi, P., Carmignoto, G., Pasti, L., Vesce, S., Rossi, D., Rizzini, B.L., Pozzan, T. and Volterra, A. (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature, 391, 281–285.PubMedCrossRefGoogle Scholar
  3. Bezzi, P., Domercq, M., Brambilla, L., Galli, R., Schols, D., De Clercq, E., Vescovi, A., Bagetta, G., Kollias, G., Meldolesi, J. and Volterra, A. (2001) CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci, 4, 702–710.PubMedCrossRefGoogle Scholar
  4. Blasi, F., Riccio, M., Brogi, A., Strazza, M., Taddei, M.L., Romagnoli, S., Luddi, A., D’Angelo, R., Santi, S., Costantino-Ceccarini, E. and Melli, M. (1999) Constitutive expression of interleukin-I beta (IL-I beta) in rat oligodendrocytes. Biol Chem, 380, 259–264.PubMedCrossRefGoogle Scholar
  5. Coco, S., Verderio, C., Trotti, D., Rothstein, J.D., Volterra, A. and Matteoli, M. (1997) Non-synaptic localization of the glutamate transporter EAAC1 in cultured hippocampal neurons. Eur J Neurosci, 9, 1902–1910.PubMedCrossRefGoogle Scholar
  6. Collaco-Moraes, Y., Aspey, B., Harrison, M. and de Belleroche, J. (1996) Cyclooxygenase-2 messenger RNA induction in focal cerebral ischemia. J Cereb Blood Flow Metab, 16, 1366–1372.PubMedCrossRefGoogle Scholar
  7. Dani, J.W., Chemjavsky, A. and Smith, S.J. (1992) Neuronal activity triggers calcium waves in hippocampal astrocyte networks. Neuron, 8, 429–440.PubMedCrossRefGoogle Scholar
  8. Dehnes, Y., Chaudhry, FA, Ullensvang, K., Lehre, K.P., Storm-Mathisen, J. and Danbolt, N.C. (1998) The glutamate transporter EAAT4 in rat cerebellar Purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J Neurosci, 18, 3606–3619.PubMedGoogle Scholar
  9. Dumuis, A., Pin, J.P., Oomagari, K., Sebben, M. and Bockaert, J. (1990) Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature, 347, 182–184.PubMedCrossRefGoogle Scholar
  10. Griffin, D.E., Wesselingh, S.L. and McArthur, J.C. (1994) Elevated central nervous system prostaglandins in human immunodeficiency virus-associated dementia. Ann Neurol, 35, 592–597.PubMedCrossRefGoogle Scholar
  11. Hassinger, T.D., Atkinson, P.B., Strecker, G.J., Whalen, L.R., Dudek, F.E., Kossel, A.H. and Kater, S.B. (1995) Evidence for glutamate-mediated activation of hippocampal neurons by glial calcium waves. J Neurobiol, 28, 159–170.PubMedCrossRefGoogle Scholar
  12. Karwoski, C.J., Lu, H.K. and Newman, E.A. (1989) Spatial buffering of light-evoked potassium increases by retinal Muller (glial) cells. Science, 244, 578–580.PubMedCrossRefGoogle Scholar
  13. Kaul, M., Garden, G.A. and Lipton, S.A. (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature, 410, 988–994.PubMedCrossRefGoogle Scholar
  14. Kimelberg, H.K., Goderie, S.K., Higman, S., Pang, S. and Waniewski, R.A. (1990) Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J Neurosci, 10, 1583–1591.PubMedGoogle Scholar
  15. Malmberg, A.B. and Yaksh, T.L. (1992) Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science, 257, 1276–1279.PubMedCrossRefGoogle Scholar
  16. Meucci, O. and Miller, R.J. (1996) gp120-induced neurotoxicity in hippocampal pyramidal neuron cultures: protective action of TGF-beta1. J Neurosci, 16, 4080–4088.PubMedGoogle Scholar
  17. Naffah-Mazzacoratti, M.G., Bellissimo, M.I. and Cavalheiro, E.A. (1995) Profile of prostaglandin levels in the rat hippocampus in pilocarpine model of epilepsy. Neurochem Int, 27, 461–466.PubMedGoogle Scholar
  18. Nedergaard, M. (1994) Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Science, 263, 1768–1771.PubMedCrossRefGoogle Scholar
  19. Noda, M., Nakanishi, H., Nabekura, J. and Akaike, N. (2000) AMPA-kainate subtypes of glutamate receptor in rat cerebral microglia. J Neurosci, 20, 251–258.PubMedGoogle Scholar
  20. Parpura, V., Basarsky, T.A., Liu, F., Jeftinija, K., Jeftinija, S. and Haydon, P.G. (1994) Glutamate-mediated astrocyte-neuron signalling. Nature, 369, 744–747.PubMedCrossRefGoogle Scholar
  21. Pasti, L., Volterra, A., Pozzan, T. and Carmignoto, G. (1997) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J Neurosci, 17, 7817–7830.PubMedGoogle Scholar
  22. Perry, V.H., Bell, M.D., Brown, H.C. and Matyszak, M.K. (1995) Inflammation in the nervous system. Curr Opin Neurobiol, 5, 636–641.PubMedCrossRefGoogle Scholar
  23. Pfrieger, F.W. and Barres, B.A. (1996) New views on synapse-glia interactions. Curr Opin Neurobiol, 6, 615–621.PubMedCrossRefGoogle Scholar
  24. Porter, J.T. and McCarthy, K.D. (1997) Astrocytic neurotransmitter receptors in situ and in vivo. Prog Neurobiol, 51, 439–455.PubMedCrossRefGoogle Scholar
  25. Rossi, D.J., Oshima, T. and Attwell, D. (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature, 403, 316–321.PubMedCrossRefGoogle Scholar
  26. Shi, B., De Girolami, U., He, J., Wang, S., Lorenzo, A., Busciglio, J. and Gabuzda, D. (1996) Apoptos is induced by HIV-1 infection of the central nervous system. J Clin Invest, 98, 1979–1990.PubMedCrossRefGoogle Scholar
  27. Steinhauser, C. and Gallo, V. (1996) News on glutamate receptors in glial cells. Trends Neurosci, 19, 339–345.PubMedCrossRefGoogle Scholar
  28. Szatkowski, M., Barbour, B. and Attwell, D. (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature, 348, 443–446.PubMedCrossRefGoogle Scholar
  29. Toggas, S.M., Masliah, E. and Mucke, L. (1996) Prevention of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine. Brain Res, 706, 303–307.PubMedCrossRefGoogle Scholar
  30. Toggas, S.M., Masliah, E., Rockenstein, E.M., Rail, G.F., Abraham, C.R. and Mucke, L. (1994) Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature, 367, 188–193.PubMedCrossRefGoogle Scholar
  31. Tsacopoulos, M. and Magistretti, P.J. (1996) Metabolic coupling between glia and neurons. J Neurosci, 16, 877–885.PubMedGoogle Scholar
  32. Ventura, R. and Harris, K.M. (1999) Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci, 19, 6897–6906.PubMedGoogle Scholar
  33. Verkhratsky, A. and Kettenmann, H. (1996) Calcium signalling in glial cells. Trends Neurosci, 19, 346–352.PubMedCrossRefGoogle Scholar
  34. Volterra, A., Bezzi, P., Rizzini, B.L., Trotti, D., Ullensvang, K., Danbolt, N.C. and Racagni, G. (1996) The competitive transport inhibitor L-trans-pyrrolidine-2, 4-dicarboxylate triggers excitotoxicity in rat cortical neuron-astrocyte co-cultures via glutamate release rather than uptake inhibition. Eur J Neurosci, 8, 2019–2028.PubMedCrossRefGoogle Scholar
  35. Waniewski, R.A. and Martin, D.L. (1986) Exogenous glutamate is metabolized to glutamine and exported by rat primary astrocyte cultures. J Neurochem, 47, 304–313.PubMedCrossRefGoogle Scholar
  36. Warr, O., Takahashi, M. and Attwell, D. (1999) Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange. J Physiol, 514 (Pt 3), 783–793.PubMedCrossRefGoogle Scholar
  37. Williams, A., Van Dam, A.M., Ritchie, D., Eikelenboom, P. and Fraser, H. (1997) Immunocytochemical appearance of cytokines, prostaglandin E2 and lipocortin-1 in the CNS during the incubation period of murine scrapie correlates with progressive PrP accumulations. Brain Res, 754, 171–180.PubMedCrossRefGoogle Scholar
  38. Williams, A.E., van Dam, A.M., Man, A.H.W.K., Berkenbosch, F., Eikelenboom, P. and Fraser, H. (1994) Cytokines, prostaglandins and lipocortin-1 are present in the brains of scrapie-infected mice. Brain Res, 654, 200–206.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Daniela Rossi
    • 1
  • Paola Bezzi
    • 1
    • 2
  • Maria Domercq
    • 1
  • Liliana Brambilla
    • 1
  • Jacopo Meldolesi
    • 3
  • Andrea Volterra
    • 1
    • 2
  1. 1.Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative DiseasesUniversity of MilanMilanItaly
  2. 2.Institute of Cell Biology and MorphologyUniversity of LausanneLausanneSwitzerland
  3. 3.Department of NeuroscienceVita-Salute San Raffaele University and Excellence Centre in Cell DifferentiationMilanItaly

Personalised recommendations