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Astrocytes, from brain glue to communication elements: the revolution continues

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.

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Figure 1: Three-dimensional view of the organization of astrocytes in separate anatomical domains.
Figure 2: Simultaneous calcium imaging of astrocytic and neuronal networks in vivo.
Figure 3: Synaptic-like microvesicles in an astrocyte process facing an excitatory synapse in the hippocampus.
Figure 4: Astrocytes exert multimodal control on synaptic transmission and neuronal excitability in the CA1 region of the hippocampus.
Figure 5: Microglia-dependent transformation of CXCR4-evoked gliotransmission into a neurotoxic pathway in AIDS-related neuropathology.

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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.).

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DATABASES

Entrez Gene

ApoE

BDNF

complexin 2

CXCR4

CX43

EphA4

GFAP

SNAP23

SNAP25

SOD1

synaptophysin

synaptotagmin I

synaptotagmin IV

TNFα

VAMP2

VAMP3

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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.

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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

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