MYELINATION Astrocytes Relay the Message

Oligodendrocytes are the glial cells that form the insulated membrane sheath called myelin on axons of the central nervous system. Electrical activity of the neurons increases myelination by stimulating differentiation of oligodendrocyte progenitor cells. This is mediated by adenosine, presumably formed from the adenosine triphosphate (ATP) released during neuronal electrical activity. Ishibashi et al. established a coculture system that allowed them to ask whether the neuron also provided instructive signals to mature oligodendrocytes, which may have important implications for alterations in myelination that occur during adulthood. Preparations of predominantly oligodendrocytes precursors (with a small percentage of astrocytes) were cocultured with dorsal root ganglion (DRG) neurons until the oligodendrocytes differentiated; then the neurons were stimulated or agonists were applied, and the percent of myelinated axons was determined. In response to stimulation of the neurons, a higher percentage of axons were myelinated than in cocultures that were not stimulated or in which action potentials were blocked. Application of the nonhydrolyzable ATP analog 2MeSATP or the P2X receptor agonist -ß methyl ATP also stimulated the increase in myelination in the absence of electrical activity, and apyrase, which hydrolyzes ATP, prevented the increase in myelination in response to electrical activity. The cytokine leukemia inhibitory factor (LIF) had been previously implicated in stimulating myelination, and Ishibashi et al. found that secretion of LIF was stimulated by electrical activity and that activity blocking antibodies against LIF prevented 2MeATP from increasing myelination. Examination of the cocultures indicated that LIF was produced by the small population of astrocytes and that the increase in transcription and secretion induced by electrical activity was blocked by apyrase. In cocultures with purified oligodendrocytes lacking any astrocytes, 2MeATP did not enhance myelination, confirming that the astrocytes were responsible for the ATP-stimulated increase in myelination. Addition of purified astrocytes, but not astrocytes from LIF-knockout mice, to the pure oligodendrocyte-DRG neuron cocultures restored the increase in myelination in response to 2MeATP. Thus, astrocytes appear to serve a key role in converting the neuronal electrical signal (mediated by released ATP) into a cytokine (LIF) signal that stimulates mature oligodendrocytes to form myelin (see Spiegel and Peles for commentary).

T. Ishibashi, K. A. Dakin, B. Stevens, P. R. Lee, S. V. Kozlov, C. L. Stewart, R. D. Fields, Astrocytes promote myelination in response to electrical impulses. Neuron 49, 823-832 (2006). [PubMed]

I. Spiegel, E. Peles, A new player in CNS myelination. Neuron 49, 777-778 (2006). [PubMed]

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PERSPECTIVES
Neuregulin-1 and Myelination

Greg Lemke (7 March 2006)
Sci. STKE 2006 (325), pe11. [DOI: 10.1126/stke.3252006pe11]
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