Switching Modes of Myelination

RESEARCH HIGHLIGHTS

MYELINATION Switching modes of myelination Neuronal activity, the neurotransmit- myelinated by forebrain oligoden- Strikingly, application of the ter glutamate and the growth factor drocytes. They assessed the overlap NMDA receptor blocker MK‑801 application neuregulin have all been implicated in the expression patterns of myelin in the presence of NRG1 led to a of the NMDA in the regulation of myelination, basic protein, which labels the dramatic reduction in myelination although their involvement in this processes of myelinating oligoden- (to a level below that seen under receptor process continues to be debated. drocytes, and neurofilaments, which control conditions). The authors blocker In a new study, Káradóttir and col- are expressed in axons, to reveal suggest that NRG1 therefore acts as MK‑801 in leagues show that myelination may myelination levels. a switch that increases the depend- the presence proceed in activity-dependent and Several studies have indi- ence of DRG axon myelination on -independent manners and that cated that neuregulin promotes neuronal activity. of NRG1 led activity-dependent myelination is myelination, although it has also How does it do this? NRG1 to a dramatic ‘switched on’ by neuregulin-induced been reported that knockout of did not elicit increased activity in reduction in signalling in oligodendrocytes, which neuregulin has no effect on this DRG neurons or have an effect on makes these cells more sensitive to process. The authors found that, in membrane resistance in oligoden- myelination glutamate release. their co-cultures, application of the drocytes. However, it did potentiate To examine the regulation of extracellular domain of neuregulin 1 NMDA receptor-mediated currents myelination, the authors used a co- (NRG1) — which activates the in oligodendrocytes by 6‑fold and culture system in which rat dorsal receptor tyrosine protein kinase thus made such cells more sensitive root ganglion (DRG) neurons are ERBB expressed on oligodendro- to glutamate. cytes — markedly increased the rate These findings may help to PhotoDisc/ Getty Images and steady-state level of myelina- resolve apparently contradictory tion. However, they also found that data from previous studies on the brain-derived neurotrophic factor involvement of neuronal activ- (BDNF) could elicit similar effects ity, glutamate and neuregulin in to NRG1 on myelination, suggesting myelination. The importance of that BDNF might compensate for the neuregulin-induced switching neuregulin in its absence. mechanism remains unclear, but Interestingly, tetrodotoxin, which the authors argue that it may enable blocked action potentials, inhibited myelination, at a certain point in the effects of NRG1 on myelination development, to be targeted to but had no effect on myelination the most active axons, limiting in co-cultures that were not treated metabolic costs. with NRG1. These findings indicate Darran Yates that myelination can occur in the

absence of neuronal activity but that ORIGINAL RESEARCH PAPER Lundgaard, I. et al. myelination in the presence of NRG1 Neuregulin and BDNF induce a switch to NMDA is, at least partly, dependent on receptor-dependent myelination by oligodendrocytes. PLoS Biol. 11, e1001743 (2013) action potentials.

NATURE REVIEWS | NEUROSCIENCE VOLUME 15 | FEBRUARY 2014