Key Points
-
Developments during the past 15–20 years have revealed surprising functions for astrocytes. This review focuses on rapid astrocytic communication, defining both modalities and roles in the healthy and diseased brain.
-
Astrocytes, which are arranged in an orderly way in discrete territories, are properly positioned for local interactions. Each astrocyte interfaces with the microvasculature and might contact several neurons, many nerve fibres and hundreds to thousands of synapses. Fractions of an astrocyte's territory can be controlled autonomously by specialized regions, such as perisynaptic processes and end-feet of the glial–vascular interface.
-
Astrocytes are 'excitable', in the sense that, when activated by internal or external signals, they deliver specific messages to neighbouring cells — an activity that has been dubbed 'gliotransmission'. Astrocytic excitation is chemically encoded, and is revealed not through electrophysiology, as for neurons, but by assays of intracellular Ca2+ concentration ([Ca2+]i) transients and oscillations.
-
Two types of astrocytic excitation have been documented: neuron-dependent excitation, which is triggered by both spill-over of synaptically released transmitters and direct neuron–glia communication; and spontaneous excitation, which occurs independently of neuronal inputs. Astrocytes discriminate different levels of neuronal activity and integrate inputs from various origins. Spontaneous [Ca2+]i changes are often of large amplitude, long duration and regular, but infrequent, occurrence.
-
Astrocytes respond to excitation by releasing gliotransmitters such as glutamate, ATP, D-serine and eicosanoids. Release occurs, at least in part, through exocytosis. Synaptic-like glutamatergic microvesicles have been identified, and their Ca2+-dependent exocytosis documented in cultured astrocytes. Astrocytic exocytosis seems to be slower and might require lower [Ca2+]i elevations than that at neuronal synapses, possibly owing to differences in the stimulus–secretion coupling and protein constituents of the machinery.
-
The release of glutamate, ATP and other gliotransmitters might occur across the plasma membrane. Three types of large ion channel — volume-regulated anion channels, gap-junctional hemichannels and P2X7 purinergic receptors — as well as the ATP-binding cassettes and cystine–glutamate exchangers, have been claimed to participate in non-exocytotic release.
-
By releasing gliotransmitters, astrocytes exert a range of non-stereotyped feedback and/or feedforward effects on neighbouring neurons, glia and blood vessels. In neuronal circuits they can fine-tune the balance between excitation and inhibition and synchronize the activity of contiguous neurons. They can also control blood flow by inducing local vasoconstriction or vasodilation responses.
-
Although astrocytes have long been known to undergo reactions to neuronal injury, until recently no specific role had been identified for these cells in the pathogenesis of brain diseases. However, alterations in the neuron–astrocyte partnership have begun to emerge, and have been shown to underlie brain lesions in pathologies as varied as brain tumours, AIDS-related neuropathology, Alzheimer's disease and amyotrophic lateral sclerosis.
Abstract
For decades, astrocytes have been considered to be non-excitable support cells of the brain. However, this view has changed radically during the past twenty years. The recent recognition that they are organized in separate territories and possess active properties — notably a competence for the regulated release of 'gliotransmitters', including glutamate — has enabled us to develop an understanding of previously unknown functions for astrocytes. Today, astrocytes are seen as local communication elements of the brain that can generate various regulatory signals and bridge structures (from neuronal to vascular) and networks that are otherwise disconnected from each other. Examples of their specific and essential roles in normal physiological processes have begun to accumulate, and the number of diseases known to involve defective astrocytes is increasing.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Colomar, A. & Robitaille, R. Glial modulation of synaptic transmission at the neuromuscular junction. Glia 47, 284–289 (2004).
Haydon, P. G. Glia: listening and talking to the synapse. Nature Rev. Neurosci. 2, 185–193 (2001).
Bushong, E. A., Martone, M. E., Jones, Y. Z. & Ellisman, M. H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22, 183–192 (2002). By injecting fluorescent dyes into contiguous hippocampal astrocytes, the authors visualized the entire structure of astrocytes and established that, contrary to common opinion, they occupy exclusive, non-overlapping territories that are evenly distributed throughout the neuropil.
Bushong, E. A., Martone, M. E. & Ellisman, M. H. Maturation of astrocyte morphology and the establishment of astrocyte domains during postnatal hippocampal development. Int. J. Dev. Neurosci. 22, 73–86 (2004).
Derouiche, A. & Frotscher, M. Peripheral astrocyte processes: monitoring by selective immunostaining for the actin-binding ERM proteins. Glia 36, 330–341 (2001).
Hirrlinger, J., Hulsmann, S. & Kirchhoff, F. Astroglial processes show spontaneous motility at active synaptic terminals in situ. Eur. J. Neurosci. 20, 2235–2239 (2004).
Benediktsson, A. M., Schachtele, S. J., Green, S. H. & Dailey, M. E. Ballistic labeling and dynamic imaging of astrocytes in organotypic hippocampal slice cultures. J. Neurosci. Methods 141, 41–53 (2005).
Simard, M., Arcuino, G., Takano, T., Liu, Q. S. & Nedergaard, M. Signaling at the gliovascular interface. J. Neurosci. 23, 9254–9262 (2003).
Mulligan, S. J. & MacVicar, B. A. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431, 195–199 (2004). This paper provides the first direct demonstration that elevated [Ca2+]i in astrocytes, which propagates as a local wave from end-foot to end-foot, can induce vasoconstriction of the surrounding arteriolar region through eicosanoid gliotransmission and the production of 20-HETE.
Sanai, N. et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427, 740–744 (2004).
Garcia, A. D., Doan, N. B., Imura, T., Bush, T. G. & Sofroniew, M. V. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nature Neurosci. 7, 1233–1241 (2004).
Bachoo, R. et al. Molecular diversity of astrocytes with implications for neurological disorders. Proc. Natl Acad. Sci. USA 101, 8384–8389 (2004).
Steinhauser, C., Berger, T., Frotscher, M. & Kettenmann, H. Heterogeneity in the membrane current pattern of identified glial cells in the hippocampal slice. Eur. J. Neurosci. 4, 472–484 (1992).
Zhou, M. & Kimelberg, H. K. Freshly isolated hippocampal CA1 astrocytes comprise two populations differing in glutamate transporter and AMPA receptor expression. J. Neurosci. 21, 7901–7908 (2001).
Nolte, C. et al. GFAP promoter-controlled EGFP-expressing transgenic mice: a tool to visualize astrocytes and astrogliosis in living brain tissue. Glia 33, 72–86 (2001).
Matthias, K. et al. Segregated expression of AMPA-type glutamate receptors and glutamate transporters defines distinct astrocyte populations in the mouse hippocampus. J. Neurosci. 23, 1750–1758 (2003).
Grass, D. et al. Diversity of functional astroglial properties in the respiratory network. J. Neurosci. 24, 1358–1365 (2004).
Wallraff, A., Odermatt, B., Willecke, K. & Steinhäuser, C. Distinct types of astroglial cells in the hippocampus differ in gap-junction coupling. Glia 48, 36–43 (2004).
Butt, A. M., Kiff, J., Hubbard, P. & Berry, M. Synantocytes: new functions for novel NG2 expressing glia. J. Neurocytol. 31, 551–565 (2002).
Bergles, D. E., Roberts, J. D., Somogyi, P. & Jahr, C. E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405, 187–191 (2000).
Lin, S. C. & Bergles, D. E. Synaptic signaling between GABAergic interneurons and oligodendrocyte precursor cells in the hippocampus. Nature Neurosci. 7, 24–32 (2004).
Golgi, C. Contribuzione alla fine anatomia degli organi centrali del sistema nervoso. Rivista Clinica di Bologna, Bologna (1871) (in French).
Seri, B., Garcia-Verdugo, J. M., McEwen, B. S. & Alvarez-Buylla, A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 21, 7153–7160 (2001).
Mauch, D. H. et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 294, 1354–1357 (2001).
Ullian, E. M., Sapperstein, S. K., Christopherson, K. S. & Barres, B. A. Control of synapse number by glia. Science 291, 657–661 (2001).
Song, H., Stevens, C. F. & Gage, F. H. Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39–44 (2002).
Hama, H., Hara, C., Yamaguchi, K. & Miyawaki, A. PKC signaling mediates global enhancement of excitatory synaptogenesis in neurons triggered by local contact with astrocytes. Neuron 41, 405–415 (2004).
Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).
Danbolt, N. C. Glutamate uptake. Prog. Neurobiol. 65, 1–105 (2001).
Oliet, S. H., Piet, R. & Poulain, D. A. Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science 292, 923–926 (2001). Shows that synaptic transmission is controlled by the astrocytic coverage of synapses. Morphological adaptations in the astrocytes are associated with changes in the perisynaptic space and in the localization of glutamate transporters, which results in modified action of synaptically released glutamate.
Piet, R., Vargova, L., Sykova, E., Poulain, D. A. & Oliet, S. H. Physiological contribution of the astrocytic environment of neurons to intersynaptic crosstalk. Proc. Natl Acad. Sci. USA 101, 2151–2155 (2004).
Lehre, K. P. & Rusakov, D. A. Asymmetry of glia near central synapses favors presynaptically directed glutamate escape. Biophys. J. 83, 125–134 (2002).
Iino, M. et al. Glia-synapse interaction through Ca2+-permeable AMPA receptors in Bergmann glia. Science 292, 926–929 (2001). By forced expression of the GluR2 subunit, the authors abolished AMPAR-dependent Ca2+ signalling in Bergmann glial cells, revealing its essential role in the establishment of correct structural-functional relationships at Purkinje cell synapses.
Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y. & Pasquale, E. B. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nature Neurosci. 6, 153–160 (2003).
Tsai, H. H. et al. The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110, 373–383 (2002).
Babcock, A. A., Kuziel, W. A., Rivest, S. & Owens, T. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J. Neurosci. 23, 7922–7930 (2003).
Marella, M. & Chabry, J. Neurons and astrocytes respond to prion infection by inducing microglia recruitment. J. Neurosci. 24, 620–627 (2004).
Imitola, J. et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1α/CXC chemokine receptor 4 pathway. Proc. Natl Acad. Sci. USA 101, 18117–18122 (2004).
Bezzi, P. & Volterra, A. A neuron–glia signalling network in the active brain. Curr. Opin. Neurobiol. 11, 387–394 (2001).
Matyash, V., Filippov, V., Mohrhagen, K. & Kettenmann, H. Nitric oxide signals parallel fiber activity to Bergmann glial cells in the mouse cerebellar slice. Mol. Cell Neurosci. 18, 664–670 (2001).
Khan, Z. U., Koulen, P., Rubinstein, M., Grandy, D. K. & Goldman-Rakic, P. S. An astroglia-linked dopamine D2-receptor action in prefrontal cortex. Proc. Natl Acad. Sci. USA 98, 1964–1969 (2001).
Araque, A., Martin, E. D., Perea, G., Arellano, J. I. & Buno, W. Synaptically released acetylcholine evokes Ca2+ elevations in astrocytes in hippocampal slices. J. Neurosci. 22, 2443–2450 (2002).
Rose, C. R. et al. Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426, 74–78 (2003).
Zhang, J. M. et al. ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 40, 971–982 (2003). This paper reveals the intermediary role of astrocytes in activity-dependent modulation of excitatory synapses in the CA1 region of the hippocampus. Stimulated by the activity of Schaffer collaterals, astrocytes release ATP, which is rapidly converted to adenosine and induces homosynaptic and heterosynaptic suppression of excitatory transmission.
Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43–50 (2003). On the basis of an ensemble of coherent evidence, this work proposes, for the first time, that astrocytes function as an intermediary of neurovascular coupling and have a key role in functional hyperaemia, the adaptation of local blood flow to neuronal activity, through the release of vasodilating prostaglandins.
Fellin, T. et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43, 729–743 (2004). Together with reference 117, this work provides the first evidence that astrocytes induce neuronal synchrony. Glutamate, which is released from astrocytes as a result of spontaneous excitation or neuronal-dependent excitation, is sensed simultaneously by two or more neighbouring CA1 pyramidal cells with the production of synchronous NMDAR-dependent SICs.
Bowser, D. N. & Khakh, B. S. ATP excites interneurons and astrocytes to increase synaptic inhibition in neuronal networks. J. Neurosci. 24, 8606–8620 (2004).
Matsui, K. & Jahr, C. E. Ectopic release of synaptic vesicles. Neuron 40, 1173–1183 (2003). This paper reports the identification of synaptic-like communication between climbing fibres and Bergmann glial cells, thereby revealing that transmitter is released from climbing fibre nerve terminals in a bimodal fashion, from conventional presynaptic sites and from ectopic sites that face the Bergmann glia.
Matsui, K. & Jahr, C. E. Differential control of synaptic and ectopic vesicular release of glutamate. J. Neurosci. 24, 8932–8939 (2004).
Araque, A., Parpura, V., Sanzgiri, R. P. & Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 22, 208–215 (1999).
Volterra, A., Magistretti, P. & Haydon, P. (eds) The Tripartite Synapse: Glia in Synaptic Transmission (Oxford Univ. Press, Oxford, UK, 2002).
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).
Grosche, J. et al. Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nature Neurosci. 2, 139–143 (1999).
Perea, G. & Araque, A. Properties of synaptically evoked astrocyte calcium signal reveal synaptic information processing by astrocytes. J. Neurosci. 25, 2192–2203 (2005). By monitoring astrocytic Ca2+ responses to the stimulation of neuronal afferents in the hippocampus, the authors found that single astrocytes can discriminate inputs that are generated by distinct sets of nerve fibres, and integrate them when they occur coincidentally.
Parri, H. R., Gould, T. M. & Crunelli, V. Spontaneous astrocytic Ca2+oscillations in situ drive NMDAR-mediated neuronal excitation. Nature Neurosci. 4, 803–812 (2001). Revealed, for the first time, that astrocytes generate spontaneous Ca2+ activity that is independent of neuronal inputs. This activity was shown to trigger neuronal excitation through the release of glutamate from the astrocytes and the induction of NMDAR-dependent SIC responses in neighbouring neurons.
Nett, W. J., Oloff, S. H. & McCarthy, K. D. Hippocampal astrocytes in situ exhibit calcium oscillations that occur independent of neuronal activity. J. Neurophysiol. 87, 528–537 (2002).
Aguado, F., Espinosa-Parrilla, J. F., Carmona, M. A. & Soriano, E. Neuronal activity regulates correlated network properties of spontaneous calcium transients in astrocytes in situ. J. Neurosci. 22, 9430–9444 (2002).
Hirase, H., Qian, L., Bartho, P. & Buzsaki, G. Calcium dynamics of cortical astrocytic networks in vivo. PLoS Biol. 2, E96 (2004). Together with reference 59, this paper provides the first report of a two-photon imaging study of spontaneous astrocytic Ca2+ activity in the brains of living animals.
Nimmerjahn, A., Kirchhoff, F., Kerr, J. N. D. & Helmchen, F. Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo. Nature Methods 1, 31–37 (2004). Illustrates a new strategy for selectively labelling astrocytes in living brains and uses it for a two-photon microscopy investigation of the [Ca2+]i dynamics in astrocytic and neuronal networks.
Sul, J. -Y., Orosz, G., Givens, R. S. & Haydon P. G. Astrocytic connectivity in the hippocampus. Neuron Glia Biol. 1, 3–11 (2004).
Newman, E. A. Propagation of intercellular calcium waves in retinal astrocytes and Müller cells. J. Neurosci. 21, 2215–2223 (2001).
Schipke, C. G., Boucsein, C., Ohlemeyer, C., Kirchhoff, F. & Kettenmann, H. Astrocyte Ca2+ waves trigger responses in microglial cells in brain slices. FASEB J. 16, 255–257 (2002).
Peters, O., Schipke, C. G., Hashimoto, Y. & Kettenmann, H. Different mechanisms promote astrocyte Ca2+ waves and spreading depression in the mouse neocortex. J. Neurosci. 23, 9888–9896 (2003).
Innocenti, B., Parpura, V. & Haydon, P. G. Imaging extracellular waves of glutamate during calcium signaling in cultured astrocytes. J. Neurosci. 20, 1800–1808 (2000).
Bernardinelli, Y., Magistretti, P. J. & Chatton, J. Y. Astrocytes generate Na+-mediated metabolic waves. Proc. Natl Acad. Sci. USA 101, 14937–14942 (2004). Shows, for the first time, that intercellular Ca2+ waves in cultured astrocytes are accompanied by parallel 'metabolic waves'. Such waves consist of [Na+]i changes that are due to glutamate uptake and coupled to glucose uptake. They could underlie spatially coordinated delivery of energy substrates to neurons in response to localized synaptic activity.
Morita, M. et al. Dual regulation of calcium oscillation in astrocytes by growth factors and pro-inflammatory cytokines via the mitogen-activated protein kinase cascade. J. Neurosci. 23, 10944–10952 (2003).
John, G. R. et al. IL-1β differentially regulates calcium wave propagation between primary human fetal astrocytes via pathways involving P2 receptors and gap junction channels. Proc. Natl Acad. Sci. USA 96, 11613–11618 (1999).
Evanko, D. S., Zhang, Q., Zorec, R. & Haydon, P. G. Defining pathways of loss and secretion of chemical messengers from astrocytes. Glia 47, 233–240 (2004).
Volterra, A. & Meldolesi, J. in Neuroglia 2nd edn (eds Kettenmann, H. & Ransom, B. R.) 190–201 (Oxford Univ. Press, Oxford, UK, 2005).
Nedergaard, M., Takano, T. & Hansen, A. J. Beyond the role of glutamate as a neurotransmitter. Nature Rev. Neurosci. 3, 748–755 (2002).
Bezzi, P. et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nature Neurosci. 7, 613–620 (2004). By combining post-embedding immunogold electron microscopy and TIRFM, this study provides the first demonstration in astrocytes of a vesicular compartment that can regulate glutamate exocytosis, and a description of its morphological and functional characteristics.
Zhang, Q. et al. Fusion-related release of glutamate from astrocytes. J. Biol. Chem. 279, 12724–12733 (2004). Using several methodological approaches, including membrane capacitance measurements in cultured astrocytes, this study and reference 73 provide evidence that complements that of reference 71 for glutamate exocytosis in astrocytes.
Kreft, M. et al. Properties of Ca2+-dependent exocytosis in cultured astrocytes. Glia 46, 437–445 (2004).
Fremeau, R. T. Jr, Voglmaier, S., Seal, R. P. & Edwards, R. H. VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci. 27, 98–103 (2004).
Montana, V., Ni, Y., Sunjara, V., Hua, X. & Parpura, V. Vesicular glutamate transporter-dependent glutamate release from astrocytes. J. Neurosci. 24, 2633–2642 (2004).
Tse, F. W. & Tse, A. Regulation of exocytosis via release of Ca2+ from intracellular stores. Bioessays 21, 861–865 (1999).
Holtzclaw, L. A., Pandhit, S., Bare, D. J., Mignery, G. A. & Russell, J. T. Astrocytes in adult rat brain express type 2 inositol 1,4,5-trisphosphate receptors. Glia 39, 69–84 (2002).
Zhang, Q., Fukuda, M., Van Bockstaele, E., Pascual, O. & Haydon, P. G. Synaptotagmin IV regulates glial glutamate release. Proc. Natl Acad. Sci. USA 101, 9441–9446 (2004).
Wilhelm, A. et al. Localization of SNARE proteins and secretory organelle proteins in astrocytes in vitro and in situ. Neurosci. Res. 48, 249–257 (2004).
Chilcote, T. J. et al. Cellubrevin and synaptobrevins: similar subcellular localization and biochemical properties in PC12 cells. J. Cell Biol. 129, 219–231 (1995).
Regazzi, R. et al. Mutational analysis of VAMP domains implicated in Ca2+-induced insulin exocytosis. EMBO J. 15, 6951–6959 (1996).
Chieregatti, E. & Meldolesi, J. Regulated exocytosis: new organelles for non-secretory purposes. Nature Rev. Mol. Cell Biol. 6, 181–187 (2005).
Chieregatti, E., Chicka, M. C., Chapman, E. R. & Baldini, G. SNAP-23 functions in docking/fusion of granules at low Ca2+. Mol. Biol. Cell 15, 1918–1930 (2004).
Dai, H. et al. Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4. Nature Struct. Mol. Biol. 11, 844–849 (2004).
Wang, C. T. et al. Different domains of synaptotagmin control the choice between kiss-and-run and full fusion. Nature 424, 943–947 (2003).
Maienschein, V., Marxen, M., Volknandt, W. & Zimmermann, H. A plethora of presynaptic proteins associated with ATP-storing organelles in cultured astrocytes. Glia 26, 233–244 (1999).
Calegari, F. et al. A regulated secretory pathway in cultured hippocampal astrocytes. J. Biol. Chem. 274, 22539–22547 (1999).
Coco, S. et al. Storage and release of ATP from astrocytes in culture. J. Biol. Chem. 278, 1354–1362 (2003).
Krzan, M. et al. Calcium-dependent exocytosis of atrial natriuretic peptide from astrocytes. J. Neurosci. 23, 1580–1583 (2003).
Mothet, J. -P. et al. Glutamate receptor activation triggers a calcium- and SNARE protein-dependent release of the gliotransmitter D-serine. Proc. Natl Acad. Sci. USA 102, 5606–5611 (2005).
Anlauf, E. & Derouiche, A. Astrocytic exocytosis vesicles and glutamate: a high-resolution immunofluorescence study. Glia 49, 96–106 (2005).
Muyderman, H. et al. α1-Adrenergic modulation of metabotropic glutamate receptor-induced calcium oscillations and glutamate release in astrocytes. J. Biol. Chem. 276, 46504–46514 (2001).
Joseph, S. M., Buchakjian, M. R. & Dubyak, G. R. Colocalization of ATP release sites and ecto-ATPase activity at the extracellular surface of human astrocytes. J. Biol. Chem. 278, 23331–23342 (2003).
Bezzi, P. et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391, 281–285 (1998).
Bezzi, P. et al. CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nature Neurosci. 4, 702–710 (2001). Reports that reactive microglia render the astrocytic Ca2+-dependent glutamate release process neurotoxic. This work also provides evidence that altered astrocyte signalling could be relevant to the pathogenesis of AIDS-related neuropathology.
Pasti, L., Zonta, M., Pozzan, T., Vicini, S. & Carmignoto, G. Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate. J. Neurosci. 21, 477–484 (2001).
Sanzgiri, R. P., Araque, A. & Haydon, P. G. Prostaglandin E(2) stimulates glutamate receptor-dependent astrocyte neuromodulation in cultured hippocampal cells. J. Neurobiol. 41, 221–229 (1999).
Zonta, M. et al. Glutamate-mediated cytosolic calcium oscillations regulate a pulsatile prostaglandin release from cultured rat astrocytes. J. Physiol. (Lond.) 553, 407–414 (2003).
Dziedzic, B. et al. Neuron-to-glia signaling mediated by excitatory amino acid receptors regulates ErbB receptor function in astroglial cells of the neuroendocrine brain. J. Neurosci. 23, 915–926 (2003).
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).
Mongin, A. A. & Kimelberg, H. K. ATP regulates anion channel-mediated organic osmolyte release from cultured rat astrocytes via multiple Ca2+-sensitive mechanisms. Am. J. Physiol. Cell Physiol. 288, C204–C213 (2005).
Bennett, M. V., Contreras, J. E., Bukauskas, F. F. & Saez, J. C. New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci. 26, 610–617 (2003).
Stout, C. E., Costantin, J. L., Naus, C. C. & Charles, A. C. Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J. Biol. Chem. 277, 10482–10488 (2002).
Arcuino, G. et al. Intercellular calcium signaling mediated by point-source burst release of ATP. Proc. Natl Acad. Sci. USA 99, 9840–9845 (2002).
Ye, Z. C., Wyeth, M. S., Baltan-Tekkok, S. & Ransom, B. R. Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J. Neurosci. 23, 3588–3596 (2003).
Duan, S. et al. P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J. Neurosci. 23, 1320–1328 (2003).
North, R. A. Molecular physiology of P2X receptors. Physiol. Rev. 82, 1013–1067 (2002).
Newman, E. A. Glial cell inhibition of neurons by release of ATP. J. Neurosci. 23, 1659–1666 (2003). In this study, an intact retinal preparation provides the first evidence that gliotransmitters other than glutamate — namely ATP rapidly converted to adenosine – induce neuronal modulation.
Wang, X. et al. P2X7 receptor inhibition improves recovery after spinal cord injury. Nature Med. 10, 821–827 (2004).
Darby, M., Kuzmiski, J. B., Panenka, W., Feighan, D. & MacVicar, B. A. ATP released from astrocytes during swelling activates chloride channels. J. Neurophysiol. 89, 1870–1877 (2003).
Rossi, D. J., Oshima, T. & Attwell, D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403, 316–321 (2000).
Baker, D. A., Xi, Z. X., Shen, H., Swanson, C. J. & Kalivas, P. W. The origin and neuronal function of in vivo nonsynaptic glutamate. J. Neurosci. 22, 9134–9141 (2002).
Cavelier, P. & Attwell, D. Tonic release of glutamate by a DIDS-sensitive mechanism in rat hippocampal slices. J. Physiol. (Lond.) 564, 397–410 (2005).
Fiacco, T. A. & McCarthy, K. D. Intracellular astrocyte calcium waves in situ increase the frequency of spontaneous AMPA receptor currents in CA1 pyramidal neurons. J. Neurosci. 24, 722–732 (2004).
Newman, E. A. & Zahs, K. R. Modulation of neuronal activity by glial cells in the retina. J. Neurosci. 18, 4022–4028 (1998).
Stevens, E. R. et al. D-serine and serine racemase are present in the vertebrate retina and contribute to the physiological activation of NMDA receptors. Proc. Natl Acad. Sci. USA 100, 6789–6794 (2003).
Kang, J., Jiang, L., Goldman, S. A. & Nedergaard, M. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nature Neurosci. 1, 683–692 (1998).
Liu, Q. S., Xu, Q., Arcuino, G., Kang, J. & Nedergaard, M. Astrocyte-mediated activation of neuronal kainate receptors. Proc. Natl Acad. Sci. USA 101, 3172–3177 (2004).
Angulo, M. C., Kozlov, A. S., Charpak, S. & Audinat, E. Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J. Neurosci. 24, 6920–6927 (2004).
Engel, A. K., Fries, P. & Singer, W. Dynamic predictions: oscillations and synchrony in top-down processing. Nature Rev. Neurosci. 2, 704–716 (2001).
Yang, Y. et al. Contribution of astrocytes to hippocampal long-term potentiation through release of D-serine. Proc. Natl Acad. Sci. USA 100, 15194–15199 (2003).
Beattie, E. C. et al. Control of synaptic strength by glial TNFα. Science 295, 2282–2285 (2002).
Filosa, J. A., Bonev, A. D. & Nelson, M. T. Calcium dynamics in cortical astrocytes and arterioles during neurovascular coupling. Circ. Res. 95, e73–e81 (2004).
Smith, I. F., Boyle, J. P., Plant, L. D., Pearson, H. A. & Peers, C. Hypoxic remodeling of Ca2+ stores in type I cortical astrocytes. J. Biol. Chem. 278, 4875–4881 (2003).
Seifert, G., Huttmann, K., Schramm, J. & Steinhauser, C. Enhanced relative expression of glutamate receptor 1 flip AMPA receptor subunits in hippocampal astrocytes of epilepsy patients with Ammon's horn sclerosis. J. Neurosci. 24, 1996–2003 (2004).
Krebs, C., Fernandes, H. B., Sheldon, C., Raymond, L. A. & Baimbridge, K. G. Functional NMDA receptor subtype 2B is expressed in astrocytes after ischemia in vivo and anoxia in vitro. J. Neurosci. 23, 3364–3372 (2003).
Contreras, J. E. et al. Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proc. Natl Acad. Sci. USA 99, 495–500 (2002).
Katsuki, H., Nonaka, M., Shirakawa, H., Kume, T. & Akaike, A. Endogenous D-serine is involved in induction of neuronal death by N-methyl-D-aspartate and simulated ischemia in rat cerebrocortical slices. J. Pharmacol. Exp. Ther. 311, 836–844 (2004).
Sontheimer, H. Malignant gliomas: perverting glutamate and ion homeostasis for selective advantage. Trends Neurosci. 26, 543–549 (2003).
Takano, T. et al. Glutamate release promotes growth of malignant gliomas. Nature Med. 7, 1010–1015 (2001). Shows that excitotoxic glutamate release from glioma cells favours tumour growth in vivo by killing neighbouring cells. The authors propose pharmacological blockade of NMDAR as a new therapeutic approach for slowing glioma expansion.
Ishiuchi, S. et al. Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nature Med. 8, 971–978 (2002).
Kaul, M., Garden, G. A. & Lipton, S. A. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410, 988–994 (2001).
Limatola, C. et al. SDF-1α-mediated modulation of synaptic transmission in rat cerebellum. Eur. J. Neurosci. 12, 2497–2504 (2000).
Zhang, K. et al. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nature Neurosci. 6, 1064–1071 (2003).
Wyss-Coray, T. et al. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nature Med. 9, 453–457 (2003). Reports that astrocytes have a crucial role in the degradation of Aβ and proposes that astrocyte defects that lead to reduced Aβ clearance are implicated in the pathogenesis of Alzheimer's disease.
Hartlage-Rubsamen, M. et al. Astrocytic expression of the Alzheimer's disease β-secretase (BACE1) is stimulus-dependent. Glia 41, 169–179 (2003).
Koistinaho, M. et al. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides. Nature Med. 10, 719–726 (2004).
Bruijn, L. I., Miller, T. M. & Cleveland, D. W. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27, 723–749 (2004).
Clement, A. M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117 (2003). By using chimaeric mice that express mixtures of normal and mutated SOD1-expressing cells, this study shows that the death of motor neurons in ALS is not a cell-autonomous process, but rather requires mutated SOD1 to be expressed in the neighbouring glial cells as well.
Pramatarova, A., Laganiere, J., Roussel, J., Brisebois, K. & Rouleau, G. A. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J. Neurosci. 21, 3369–3374 (2001).
Lino, M. M., Schneider, C. & Caroni, P. Accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. J. Neurosci. 22, 4825–4832 (2002).
Gong, Y. H., Parsadanian, A. S., Andreeva, A., Snider, W. D. & Elliott, J. L. Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J. Neurosci. 20, 660–665 (2000).
Howland, D. S. et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc. Natl Acad. Sci. USA 99, 1604–1609 (2002).
Rothstein, J. D et al. β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005).
Ikeda, H. & Murase, K. Glial nitric oxide-mediated long-term presynaptic facilitation revealed by optical imaging in rat spinal dorsal horn. J. Neurosci. 24, 9888–9896 (2004).
Raoul, C. et al. Motoneuron death triggered by a specific pathway downstream of Fas: potentiation by ALS-linked SOD1 mutations. Neuron 35, 1067–1083 (2002).
Jabaudon, D. et al. Inhibition of uptake unmasks rapid extracellular turnover of glutamate of nonvesicular origin. Proc. Natl Acad. Sci. USA 96, 8733–8738 (1999).
Steyer, J. A. & Almers, W. A real-time view of life within 100 nm of the plasma membrane. Nature Rev. Mol. Cell Biol. 2, 268–275 (2001).
Parpura, V. et al. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747 (1994).
Hussy, N. et al. Osmoregulation of vasopressin secretion via activation of neurohypophysial nerve terminals glycine receptors by glial taurine. J. Neurosci. 21, 7110–7116 (2001).
Do, K. Q. et al. Release of homocysteic acid from rat thalamus following stimulation of somatosensory afferents in vivo: feasibility of glial participation in synaptic transmission. Neuroscience 124, 387–393 (2004).
Smit, A. B. et al. A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature 411, 261–268 (2001).
Acknowledgements
The authors wish to thank P. Bezzi for comments on the manuscript. The authors' work is supported by grants from the Swiss National Fund for Scientific Research and the Swiss State Secretariat for Education and Research to A.V., from the Fondo Investimenti per la Ricerca di Base of the Italian Ministry of Research and the VI Framework Programme of the European Union to J.M., and grants from the Italian Telethon Foundation (J.M. and A.V.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Related links
Related links
DATABASES
Entrez Gene
FURTHER INFORMATION
Glossary
- BERGMANN GLIAL CELLS
-
(Also known as Golgi epithelial cells). These are the radial astrocytes of the cerebellum. Their highly branched processes make complex interactions with the synapses on Purkinje cell dendrites.
- VOLUME-REGULATED ANION CHANNELS
-
(VRACs). Channels activated not by voltage changes or ligand binding but by the swelling of the cell. They are permeant to monovalent anions and organic osmolytes, such as amino acids and polyols.
- GAP-JUNCTION HEMICHANNELS
-
(Also known as connexons). Large, non-selective ion channels composed of connexin subunits. They can reside in the plasma membrane autonomously, or be coupled with a hemichannel of an adjacent cell to form a gap junction.
- PURINERGIC P2X7 RECEPTOR
-
A plasma membrane channel that is activated by the binding of ATP and is permeant to mono- and divalent cations. In many cells, on sustained stimulation, the aqueous pore dilates to admit larger molecules irrespective of their charge.
- ATP-BINDING CASSETTES
-
(ABC proteins). A superfamily of integral membrane proteins that bind and hydrolyse ATP. Most function to translocate specific substrates across cell membranes.
- HIGH-AFFINITY GLUTAMATE TRANSPORTERS
-
A family of proteins in the plasma membrane of astrocytes and neurons with the specific function of removing glutamate from the extracellular fluid. For each transport cycle, together with one glutamate molecule, they co-transport three Na+ ions and one H+ ion, and countertransport one K+ ion.
- CYSTINE/GLUTAMATE EXCHANGER
-
A Na+-independent amino acid antiporter that exchanges extracellular cystine for intracellular glutamate. These exchangers are ubiquitous in brain cells, and each comprises two separate proteins: a light chain that confers specificity, and a heavy chain.
- AMMON'S HORN SCLEROSIS
-
A brain lesion that is characterized by neuronal loss and reactive gliosis — which forms a 'scar' — localized in Ammon's horn of the hippocampus.
Rights and permissions
About this article
Cite this article
Volterra, A., Meldolesi, J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6, 626–640 (2005). https://doi.org/10.1038/nrn1722
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrn1722
This article is cited by
-
d-Cycloserine enhances the bidirectional range of NMDAR-dependent hippocampal synaptic plasticity
Translational Psychiatry (2024)
-
Possible roles of deep cortical neurons and oligodendrocytes in the neural basis of human sociality
Anatomical Science International (2024)
-
Changes at glutamate tripartite synapses in the prefrontal cortex of a new animal model of resilience/vulnerability to acute stress
Translational Psychiatry (2023)
-
Analog neuromorphic circuit for spontaneous Ca2+ oscillations
Scientific Reports (2023)
-
Revisiting the critical roles of reactive astrocytes in neurodegeneration
Molecular Psychiatry (2023)