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Astrocytes Promote Myelination in Response to Electrical Impulses View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Neuron 49, 823–832, March 16, 2006 ª2006 Elsevier Inc. DOI 10.1016/j.neuron.2006.02.006 Astrocytes Promote Myelination in Response to Electrical Impulses Tomoko Ishibashi,1 Kelly A. Dakin,1 Beth Stevens,1 merens et al., 1996). More recent evidence suggests that Philip R. Lee,1 Serguei V. Kozlov,2 Colin L. Stewart,2 activity-dependent effects on myelination may regulate and R. Douglas Fields1,* nervous system function according to functional and 1 Nervous System Development and Plasticity Section cognitive activity (Schmithorst et al., 2005), learning National Institute of Child Health and Human (Bengtsson et al., 2005), and environmental input (Mark- Development ham and Greenough, 2004). For review see Fields (2005). Bethesda, Maryland 20892 How, at a molecular and cellular level, impulse activity 2 Laboratory of Cancer and Developmental Biology promotes myelination by mature oligodendrocytes, is National Cancer Institute an important question. Frederick, Maryland 21702 Two general molecular mechanisms have been re- vealed for activity-dependent effects on early stages of myelination: activity-dependent regulation of cell ad- Summary hesion molecule expression in neurons that are neces- sary for myelination (Itoh et al., 1995, Stevens et al., Myelin, the insulating layers of membrane wrapped 1998) and the release of diffusible signaling molecules around axons by oligodendrocytes, is essential for from axons firing action potentials, which activate re- normal impulse conduction. It forms during late ceptors on premyelinating glia and influence their prolif- stages of fetal development but continues into early eration and differentiation (Fields and Stevens, 2000; adult life. Myelination correlates with cognitive devel- Stevens et al., 2002). Molecular mechanisms for effects opment and can be regulated by impulse activity of impulse activity on myelination at later stages of de- through unknown molecular mechanisms. Astrocytes velopment are unknown. do not form myelin, but these nonneuronal cells can Purinergic signaling, mediated by the activity-depen- promote myelination in ways that are not understood. dent release of ATP from axons (Stevens and Fields, Here, we identify a link between myelination, astro- 2000) and the subsequent hydrolysis to adenosine (Ste- cytes, and electrical impulse activity in axons that is vens et al., 2002), is one of the principal mechanisms of mediated by the cytokine leukemia inhibitory factor activity-dependent communication between axons and (LIF). These findings show that LIF is released by myelinating glia (Fields, 2006). ATP released from axons astrocytes in response to ATP liberated from axons fir- firing action potentials inhibits myelination by Schwann ing action potentials, and LIF promotes myelination cells by arresting their development at an early stage by mature oligodendrocytes. This activity-dependent (Fields and Stevens, 2000). In the CNS, adenosine, pre- mechanism promoting myelination could regulate sumably generated by the hydrolysis of extracellular myelination according to functional activity or envi- ATP released from axons, inhibits proliferation of oligo- ronmental experience and may offer new approaches dendrocyte progenitor cells (OPCs), and stimulates their to treating demyelinating diseases. differentiation into a premyelinating stage, thus increas- ing myelination (Stevens et al., 2002). In both cases, ac- Introduction tion potentials influence myelination by regulating matu- ration of immature premyelinating glia. The possible There is growing awareness that activity-dependent in- activity-dependent communication and effects on oligo- teractions between glia and synapses are important dendrocytes that are already differentiated to a promye- for nervous system development and function (Fields linating stage have not been explored. and Stevens-Graham, 2002; Fields, 2004), but compara- The object of the present series of experiments was to tively little is known of activity-dependent interactions determine if neural impulse activity can influence myeli- between axons and myelinating glia. These glial cells nation at later stages of oligodendrocyte development, are far removed from synapses where neurotransmitter independent of the known effects of adenosine on could act as a neuron-glial signal, and the mechanisms OPC differentiation (Stevens et al., 2002). An activity-de- regulating myelination are still unclear. Myelination by pendent effect on myelination after OPCs have matured oligodendrocytes in the CNS and Schwann cells in the could have relevance to treating demyelinating disease PNS is essential for nervous system function in verte- and to use-dependent effects on myelination. The re- brates, and myelin organizes the distribution of ion sults reveal a new mechanism by which action poten- channels along the axon to provide the electrical proper- tials influence myelination. This involves unexpected in- ties necessary for saltatory impulse conduction (Dupree teractions between astrocytes and myelinating glia and et al., 2004). Myelination is a highly regulated develop- between purinergic and cytokine signaling. mental process, but it also takes place postnatally and continues into early adult life (Yakovlev and Lecours, Results and Discussion 1967; Giedd, 2004). As with synaptic remodeling during this period, evidence suggests that action potential fir- To determine effects of action potentials on myelination ing can influence myelination (Zalc and Fields, 2000; De- after oligodendrocytes have matured well beyond the progenitor stage, we conducted experiments in special culture dishes (Campenot chambers) equipped for elec- *Correspondence: fi[email protected] trical stimulation (Figure 1A). After 3–4 weeks in culture, Neuron 824 Figure 1. Action Potentials Stimulate Myeli- nation of DRG Axons by Mature Oligodendro- cytes (A) Mouse DRG neurons were cultured 3–4 weeks in multicompartment culture dishes equipped with electrodes for stimulating ac- tion potentials in axons. Axons from DRG neurons plated into the two-side compart- ments grow under the barrier with the central compartment, providing a high resistance connection for electrical stimulation through platinum electrodes (Fields et al., 1992). Oli- godendrocyte progenitor cells (OPCs) were added to the side compartments and cul- tured with DRG neurons for 7 days. Electrical stimulation in a phasic pattern (see Experi- mental Procedures) was applied to axons for 2–3 weeks, and the number of myelinated profiles stained with Sudan black was com- pared with unstimulated controls. (B) Electrical stimulation increased myelina- tion through a mechanism requiring activa- tion of sodium-dependent action potentials, as shown by blocking the effects of stimula- tion in the presence of 1 mM of the sodium channel blocker tetrodotoxin (TTX). (C) Treating cultures of mature oligodendro- cytes and DRG neurons with adenosine (300 mM) or the adenosine receptor agonist NECA over a wide range of concentrations failed to increase the number of Sudan-black-stained myelin profiles, but treatment with the ATP receptor agonist 2MeSATP (300 mM) mimicked the effect of electrical stimulation in increasing myelination by oligodendrocytes (n = 156 cultures, eight independent experiments). ATP is known to be released by axons firing action potentials (Stevens and Fields, 2000), suggesting that ATP may be an activity-dependent intercellular mes- senger regulating myelination. (D) A similar increase in myelination was seen by using immunocytochemical staining with antibodies against myelin oligodendrocyte glycopro- tein (MOG) to quantify the number of myelin segments/microscope field in unstimulated (1Ca) and stimulated cultures (1Cb) (24 cultures, three independent experiments). p < 0.005 with respect to control; scale bar = 20 mm. Error bars represent SEM. OPCs were added to DRG neurons and co-cultured to- and 1D) (p < 0.005). Electrical stimulation combined with gether for 7 days to allow sufficient time for OPCs to dif- 2MeSATP treatment produced no further increase in ferentiate to the oligodendrocyte stage. Axons were myelination, suggesting that electrical activity and ATP then stimulated with a pattern of electrical activity (0.5 s receptor activation may increase myelination by acting at 10 Hz, every 2 s), which is known to stimulate release through the same mechanism (Figure 2A). Because of ATP from axons (Stevens and Fields, 2000). 2 weeks these cultures were treated with ATP receptor agonists later, myelination was assessed and found to have in- after the oligodendrocytes had already matured to a pro- creased 3-fold on axons firing action potentials com- myelinating stage, the increased myelination must be pared with unstimulted controls, or axons stimulated due to effects other than promoting differentiation in the presence of TTX, which blocks sodium-dependent from the immature stage, in contrast to the actions of action potentials (Figure 1B) (p < 0.001). adenosine (Stevens et al., 2002). (This was confirmed Thus, action potential firing in axons can increase by staining the cocultures with markers of oligodendro- myelination after oligodendrocytes have developed be- cyte differentiation. There was no significant difference yond the progenitor stage. It would be difficult to explain in the proportion of cells stained for NG2, O4, and O1 this result by previous studies reporting that activity-de- compared with controls,
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