Neuroscience

A mechanism for myelin injury

The cells that insulate neuronal processes with a myelin membrane sheath are damaged during stroke. Data now show that an influx of calcium ions mediated by the TRPA1 protein contributes to myelin injury. See Letter p.523

Normal brain function requires the rapid transmission of information between brain regions along neuronal projections called axons. The ability of axons to conduct information depends on the well-being of a supporting class of glial cells called oligodendrocytes1, which speed up conduction by enveloping the axonal projections in a multilayered membrane sheath called myelin. Damage to oligodendrocytes and the myelin sheaths that they produce has been associated with axonal dysfunction in numerous disorders, including cerebral palsy, spinal-cord injury, multiple sclerosis and stroke. In this issue, Hamilton et al.2 (page 523) report that the mechanisms that underlie this damage are more complex than commonly thought and involve the activation of a channel protein called TRPA1.

During a stroke, the local loss of blood flow in the brain, known as ischaemia, causes damage to neurons and glial cells, including oligodendrocytes. Even transient ischaemia causes permanent defects in axonal conductivity that can be only partially restored when the supply of oxygen and glucose to the tissue is re-established3. Ischaemia causes the release of the neurotransmitter molecule glutamate, which excites oligodendrocytes. Some evidence3,4,5 indicates that blocking glutamate-receptor proteins reduces myelin damage and axon dysfunction during ischaemia. AMPA/kainate-type and NMDA-type glutamate receptors are ion-channel proteins that, when activated, allow positively charged ions such as sodium (Na+) and calcium (Ca2+) to flow into the cell. High levels of Ca2+ are toxic to cells, and so the death of oligodendrocytes and injury to myelin sheaths during ischaemia are widely thought to reflect the overactivation of these glutamate receptors5,6,7 — the same mechanism by which ischaemia damages neurons.

Hamilton et al. revisited this issue in brain slices from the rat cerebellum. They found evidence that, in the cerebellar white matter (a tissue that contains a high density of myelinated axons) deprivation of oxygen and glucose — a model of ischaemia-evoked oligodendrocyte and myelin damage — might not result in glutamate-receptor overactivation alone. First, the authors characterized ischaemia-evoked membrane currents in oligodendrocytes and monitored the corresponding intracellular changes in Ca2+, Na+, potassium ions (K+) and magnesium ions. Strikingly, although oxygen and glucose deprivation did cause an inward flow of ions in oligodendrocytes that was mediated by glutamate release, this current flow seemed to be triggered by an increase in extracellular K+ concentration and closure of K+-channel proteins, rather than by glutamate receptors.

Similar to an earlier report5, Hamilton and colleagues found that ischaemia led to an increase in intracellular Ca2+ levels in oligodendrocytes and their axon-ensheathing processes. However, inhibition of NMDA and AMPA/kainate receptors did not prevent Ca2+ influx. These data suggest that glutamate receptors are not the primary channels responsible for the ischaemia-evoked elevations of Ca2+ concentrations that cause myelin damage.

Next, the authors demonstrated that the ischaemia-evoked elevation of extracellular K+ levels leads to increased hydrogen-ion levels (acidification) in oligodendrocytes that in turn triggers Ca2+ influx (Fig. 1). By increasing local intracellular H+ levels in oligodendrocytes and measuring intracellular Ca2+ changes, Hamilton et al. investigated which other channels might contribute to ischaemia-evoked Ca2+ influx. After taking into account the known physiological properties of different ion-channel proteins and testing the effects of channel stimulators and inhibitors, the authors concluded that the channel responsible is TRPA1 — a widely expressed member of the family of transient receptor potential (TRP) channels (Fig. 1). Activation of TRPA1 channels allows Ca2+, Mg2+ and Na+ to enter the cell.

Figure 1: Myelin injury in a model of ischaemia.
figure1

Oligodendrocyte cells wrap around neurons and produce an insulating stack of membranes called myelin that speeds up neuronal signal transmission. When brain regions are deprived of glucose and oxygen (a condition called ischaemia), oligodendrocytes and myelin become damaged. Hamilton et al.2 report that this damage is caused, in part, by a pathway that involves an increase in extracellular levels of potassium ions (K+). Through an unknown mechanism (dashed arrow), increased K+ levels trigger an intracellular rise in hydrogen ions (H+). This reduces the pH in the cell, activating TRPA1-channel proteins and leading to an influx of calcium ions (Ca2+). High levels of Ca2+ are toxic to oligodendrocytes and damage myelin. Glutamate-receptor proteins such as NMDA-type receptors can also mediate Ca2+ influx, but whether they have a role in ischaemia-evoked myelin damage in this setting is unclear.

In line with Hamilton and colleagues' conclusion, ischaemia-triggered Ca2+ entry was considerably reduced in white-matter cerebellum slices from mice in which TRPA1 had been deleted. However, the authors did not test the in vivo effects of ischaemia on white matter in these mice. Instead, using isolated optic nerves from rats, the authors showed that blocking TRPA1 channels during oxygen and glucose deprivation reduced myelin damage, but had no effect on axonal injury. Thus, unlike the case with oligodendrocytes, damage to axons is mediated not by the activation of TRPA1 channels, but by other mechanisms of Ca2+ influx.

Hamilton et al. also detected spontaneous Ca2+-level changes in the myelin of some normal oligodendrocytes, which were not deprived of glucose and oxygen. This spontaneous activity is probably indicative of axonal activity and the concurrent release of glutamate. So, given that myelin contains AMPA/kainate and NMDA receptors5,6,7, and that ischaemia-evoked Ca2+-level changes in optic nerves have previously been shown to be caused by activation of glutamate receptors5, why did the authors not find evidence for glutamate-evoked Ca2+ changes?

The levels of the messenger RNAs that encode NMDA receptors are low in mature oligodendrocytes, but the levels of TRPA1 mRNA are almost undetectable8, and the researchers still detected TRPA1-mediated Ca2+ influx in cerebellar oligodendrocytes. Evidence indicates that NMDA receptors move to myelin processes that face the axonal surface as oligodendrocytes mature5,6. This might help to explain why glutamate-evoked Ca2+ responses are difficult to detect in oligodendrocytes. Alternatively, perhaps oligodendrocytes in the optic nerve, which myelinate axons of only glutamate-releasing neurons, are different from the cerebellar oligodendrocytes that also myelinate neurons producing a different neurotransmitter, GABA.

In contrast to the current paper, a study published last month9 provided evidence that, in optic nerves, NMDA and AMPA/kainate receptors do indeed act to mediate Ca2+ influx in mature myelin. Such influx in myelin is mediated by axonal activity and the vesicular release of glutamate. However, beyond the level of Ca2+ signals, the physiological functions of oligodendroglial NMDA receptors still need to be resolved.

Hamilton and colleagues' study demonstrates that in vitro damage to myelin owing to oxygen and glucose deprivation is more complex than anticipated, with TRPA1 channels joining the scene. Whether the results apply in vivo or to human TRPA1 channels, which have a different pharmacological response from those of mice10, remains to be seen. Trials of NMDA-receptor blockers in people who have had a stroke have largely failed, in part because the drugs were administered too late, given the low doses at which their adverse side effects can be tolerated. Identifying other pharmacological targets raises the hope that safer drugs may be found.Footnote 1

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Correspondence to Aiman S. Saab or Klaus-Armin Nave.

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Saab, A., Nave, KA. A mechanism for myelin injury. Nature 529, 474–475 (2016). https://doi.org/10.1038/nature16865

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