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Glia: listening and talking to the synapse

Nature Reviews Neuroscience volume 2, pages 185–193 (2001)Cite this article

Key Points

  • Glial cells have been largely regarded as merely the supportive elements in the nervous system. However, recent evidence indicates that the glia have an active role in modulating synaptic transmission. In fact, communication between neurons and glia is bidirectional, as neuronal activity can elicit changes in glial calcium levels.

  • Different molecules released by neurons can affect intracellular Ca2+ levels in glial cells. Glutamate has received a lot of attention in this regard, and it has been shown to modulate glial Ca2+ levels both in culture and in situ.

  • The increases in Ca2+ levels experienced by individual glial cells can propagate across large distances in the form of Ca2+ waves. The mechanism of propagation seems to involve both intracellular and extracellular signals (inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) and ATP, respectively). It is likely that Ins(1,4,5)P3 diffusion through gap junctions is important for short-range wave propagation, whereas ATP might be more relevant for propagation across larger distances.

    • ATP is not the only transmitter released by astrocytes. This cell type can also release glutamate in a calcium-dependent manner that probably involves exocytosis. d-serine is another molecule released by astrocytes, although its release mechanism is not known. Similarly, the pathway responsible for ATP release remains to be discovered but is unlikely to involve vesicle fusion.

  • Transmitters released by astrocytes can modulate synaptic transmission, giving rise to the concept of 'tripartite synapses'. Evidence regarding this modulation has been obtained both in culture and in situ, and it seems to affect basal synaptic transmission, as well as plastic phenomena. Moreover, glial cells can also modulate neuronal activity through a direct pathway that involves gap junctions between neurons and glia.

  • The reciprocal communication between neurons and glia adds degrees of freedom to brain function. For example, increases in astrocytic calcium elicited by the activity of a given synapse could affect the function of synapses at distant locations through the spread of the calcium signal within the same astrocyte. Is this phenomenon ever observed in situ ? What are the functional consequences of this lateral, much slower, signalling pathway? Future experiments will aim to address these questions.

Abstract

Glial cells are emerging from the background to become more prominent in our thinking about integration in the nervous system. Given that glial cells associated with synapses integrate neuronal inputs and can release transmitters that modulate synaptic activity, it is time to rethink our understanding of the wiring diagram of the nervous system. It is no longer appropriate to consider solely neuron–neuron connections; we also need to develop a view of the intricate web of active connections among glial cells, and between glia and neurons. Without such a view, it might be impossible to decode the language of the brain.

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Figure 1: Glial cells make intimate contact with synaptic terminals.
Figure 2: Neuronal stimulation causes a neurotransmitter-dependent elevation of astrocytic Ca2+.
Figure 3: Stimulation of glial cells from the retina evokes a radially propagating wave of elevated calcium.
Figure 4: Astrocytic calcium waves cause the calcium-dependent release of glutamate.
Figure 5: G-protein-mediated signalling in synaptically associated perisynaptic Schwann cells depresses neuromuscular transmission.
Figure 6: Intercellular signalling between neurons and astrocytes can have a local modulatory action, as well as participate in the communication between distant synapses.

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Acknowledgements

P.G.H. wishes to thank R. Doyle, H. Chen and J.-Y. Sul for comments on an earlier version of this manuscript, and V. Parpura, S. Shen, M. McCloskey and D. Sakaguchi for their stimulating discussions at various stages of these studies. Work done by P.G.H. is supported by grants from the National Institutes of Health.

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  1. Department of Zoology and Genetics, Iowa State University, Ames, 50011, Iowa, USA

    Philip G. Haydon

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PLC

P2Y1

IL-1β

P2Y2

connexin 43

FURTHER INFORMATION

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Glossary

PROSTAGLANDINS

Biologically active metabolites of arachidonic acid and other lipids. Prostaglandins have many functions; for example, they are involved in vasodilation, bronchodilation, inflamatory reactions and the regulation of cell proliferation.

BERGMANN GLIA

The main glial cell type present in the cerebellum.

SCHAFFER COLLATERALS

Axons of the CA3 pyramidal cells of the hippocampus that form synapses with the apical dendrites of CA1 neurons.

MĂśLLER GLIA

The main glial cell type present in the retina.

GAP JUNCTIONS

Cellular specializations that allow the passage of small molecules between the cytoplasm of adjacent cells. They are formed by channels termed connexons, multimeric complexes of proteins known as connexins.

CAGED INS(1,4,5)P3

In general terms, a caged molecule is a labile derivative of a biologically active molecule that will break down after appropriate (commonly luminous) stimulation to yield the bioactive compound.

LUCIFERIN–LUCIFERASE ASSAY

Method to detect the presence of ATP, which is based on the ability of the firefly enzyme luciferase to catalyse a reaction between its substrate luciferin and ATP and release the two terminal phosphate groups of ATP. Luciferin becomes excited during the process but, on return to its basal state, it releases energy in the form of light.

INTERLEUKIN-1β

Signalling molecule involved in the inflammatory response that can act as an endogenous pyrogen.

ENDOTHELIN

Molecule with potent vasoconstrictor activity. It is expressed by vascular cells, as well as in brain, kidney and lung.

ANANDAMIDE

An endogenous agonist of cannabinoid receptors.

TETANUS TOXIN

Protein derived from Clostridium tetani that can block transmitter release owing to its ability to degrade synaptobrevin. Tetanus toxin is the causative agent of tetanus.

PARALLEL FIBRES

The axons of cerebellar granule cells. Parallel fibres emerge from the molecular layer of the cerebellar cortex towards the periphery, where they extend branches perpendicular to the main axis of the Purkinje neurons and form the so-called en passant synapses with this cell type.

LOCUS COERULEUS

Nucleus of the brainstem. The main provider of noradrenaline to the brain.

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Haydon, P. Glia: listening and talking to the synapse. Nat Rev Neurosci 2, 185–193 (2001). https://doi.org/10.1038/35058528

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