Purinergic signalling in neuron–glia interactions

^{National Institute of Child Health and Human Development, National Institutes of Health, Building 35, Room 2A211, MSC 3713, 35 Lincoln Drive, Bethesda, Maryland 20892, USA}

^{Autonomic Neuroscience Centre, Royal Free and University College Medical School, Rowland Hull Street, London NW3 2PF, UK}

Correspondance to R.D.F. e-mail: vog.hin.liam@dsdleif

Abstract

Activity-dependent release of ATP from synapses, axons and glia activates purinergic membrane receptors that modulate intracellular calcium and cyclic AMP. This enables glia to detect neural activity and communicate among other glial cells by releasing ATP through membrane channels and vesicles. Through purinergic signalling, impulse activity regulates glial proliferation, motility, survival, differentiation and myelination, and facilitates interactions between neurons, and vascular and immune system cells. Interactions among purinergic, growth factor and cytokine signalling regulate synaptic strength, development and responses to injury. We review the involvement of ATP and adenosine receptors in neuron–glia signalling, including the release and hydrolysis of ATP, how the receptors signal, the pharmacological tools used to study them, and their functional significance.

Abstract

Functional interactions between neurons and glia have been suspected for decades, but how glia might detect neural activity, communicate with other glial cells, and influence neuronal function have proved to be difficult questions to answer. Before purinergic signalling was considered, several other mechanisms were explored for neuron–glia communication, but each of these was comparatively limited. Astrocytes can communicate through gap junctions¹, but this was viewed in the context of maintaining homeostasis of extracellular potassium. Bursts of action potentials fired by axons release potassium, which is taken up by astrocytes and dispersed through an astrocytic syncytium coupled by gap junctions. The build up of potassium during prolonged high-frequency stimulation can produce calcium transients in myelinating glia (Schwann cells) in the sciatic nerve², but stimulation in the normal physiological range does not have this effect. Glial membrane receptors can be activated by many different neurotransmitters³, although this is most relevant to glia having access to neurotransmitter spreading beyond the synaptic cleft⁴. Purinergic signalling has emerged as the most pervasive mechanism for intercellular communication in the nervous system, affecting communication between many types of neurons, all types of glia, and vascular cells⁵6.

Here we examine the history and recent developments of neuron–glia signalling and the prominent role of extracellular ATP in these interactions. We review the mechanisms of ATP release from cells and the large family of membrane receptors for extracellular ATP and adenosine. The pharmacology and expression of these receptors in glia are summarized, and the consequences of purinergic signalling in neuron–glia communication are discussed, with an emphasis on glial regulation of synaptic transmission, activity-dependent myelination, and nervous system response to injury.

Footnotes

Competing interests statement

The authors declare no competing financial interests.

DATABASES

The following terms in this article are linked online to:

Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene

BDNF | GFAP

OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

Alexander disease | Alzheimer’s disease | Parkinson’s disease

FURTHER INFORMATION

Fields’s laboratory: http://nsdps.nichd.nih.gov/

Burnstock’s laboratory: http://www.ucl.ac.uk/ani

Footnotes

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