18 March 2006. Behind every successful neuron, there are dozens of good glia. Far from being an inert scaffold, astrocytes and microglia are increasingly recognized to be active participants in the life and death of neurons (see related ARF Live Discussion). Now, work from the lab of developmental neurobiologist R. Douglas Fields reveals a new and unexpected role for astrocytes in the myelination of axons in the central nervous system. In a report in the March 16 Neuron, Fields and colleagues at the National Institute of Child Health and Human Development in Bethesda and the National Cancer Institute in Frederick, Maryland, show that the activity-dependent myelination of neurons in culture by mature oligodendrocytes requires astrocytes. Specifically, the astrocytes respond to ATP produced by electrically stimulated axons by themselves producing the cytokine leukemia inhibitory factor (LIF), which in turn stimulates oligodendrocytes to increase myelination.
As pointed out in an accompanying commentary by Ivo Spiegel and Elior Peles of the Weizmann Institute, Rehovot, Israel, the study raises the intriguing possibility that glial cells can participate in activity-dependent plasticity of myelination in mature neurons. Such a scenario would present new opportunities to intervene in demyelinating diseases like multiple sclerosis. Perhaps it could also help explain the demyelination that occurs in Alzheimer disease, possibly in response to changes in neural activity.
Myelination of axons by oligodendrocytes occurs mainly during nervous system development, but it continues into adulthood for some nerves. Early on, electrical activity regulates myelination via adenosine-mediated effects on oligodendrocyte proliferation and differentiation. However, the regulation of myelination later, by mature oligodendrocytes, has not been as well understood.
Using an in-vitro system where dorsal root ganglion (DRG) explants and mature oligodendrocytes were cultured together in a special chamber, first author Tomoko Ishibashi was able to show a threefold increase in myelination when the DRG neurons were electrically stimulated. Adding a non-hydrolyzable ATP analog to cultures mimicked this result, and further experiments showed that increased myelination by either the ATP analog or electrical stimulation required the cytokine LIF, which was being produced in the cultures.
That production was traced to astrocytes, and Ishibashi et al. showed that the ATP released from neurons as a result of electrical activity increased LIF mRNA in, and release from, astrocytes. To prove the astrocytes were indispensable, they repeated the experiments in cultures lacking these cells, and showed myelination could not be stimulated. Adding back astrocytes restored the effect, but not if they came from LIF knockout mice.
The results could explain defects in myelination found in either GFAP knockout mice, which lack astrocytes, and also in LIF knockout mice. In each case, the phenotypes support a role of astrocytes in modulating myelination, rather than as primary regulators. “Taken together, these results reveal a new mechanism by which electrical activity promotes myelination of CNS axons at a later developmental stage and possibly into postnatal life,” the authors conclude.—Pat McCaffrey.
Ishibashi T, Dakin KA, Stevens B, Lee PR, Kozlov SV, Stewart CL, Fields RD. Astrocytes Promote Myelination in Response to Electrical Impulses. Neuron. 16 March 2006; 49: 823-832. Abstract
Spiegel I, Peles E. A New Player in CNS Myelination. Neuron. 16 March 2006;
49: 777-778. Abstract