Axonal activity biases myelination by oligodendrocytes in the central nervous system

Oligodendrocytes myelinate central nervous system (CNS) axons during development and other process involved in axonal plasticity. However, not all CNS axons are myelinated by oligodendrocytes. Some evidence suggests oligodendrocytes may myelinate or maintain myelination of axons of a specific caliber (size).  Other studies also suggest oligodendrocytes sustain myelination of axons based on chemical cues secreted by axons, alone and in combination with size selectivity. Still, other results indicate electrical activity pf axons can stimulate oligodenrocytes to myelinate active axons. Despite all of these ideas, no clear mechanisms of how oligodendrocytes choose to myelinate or sustain myelination of particular axons is available. A recent study by Hines et al. in Nature Neuroscience (April, 2015; doi:10.1038/nn.3992) provides convincing evidence that oligodendrocytes initially myelinate various axons, but maintain myelination of axons through a bias based on activity of the axons.

Using transgenic mice that allow fluorescent identification of oligodendrocytes and a specific subset of hindbrain axons that project to the spinal cord in zebrafish (phox2b+ axons), the researchers observed that application of tetrodotoxin (TTX), a voltage-gated sodium channel blocker that effectively paralyzes axonal activity, did not affect oligodendrocyte survival or numbers, but did affect axonal selectivity of myelination. By treating the fish larvae with sodium channel modulator, veratridine 72 h post-fertilization (just before onset of myelination) causes widespread neuronal and axon activity, but does not significantly effect the selection of axons for myelination. However, it did affect sheath length.

The authors then utilized targeted overexpression via viral transfection of the human inward rectifier K⁺ channel Kir2.1 in single phox2b⁺ axons, which reduces neuronal and axon excitability in the zebrafish to determine whether neuronal excitability was necessary for axon selection for myelination. They found that the Kir2.1 reduced animals had significantly decreased myelination by oligodendrocytes. Using confocal microscopy, the authors determined that fluorescently labeled (EGFP) vesicles accumulated at myelin ensheathment sites, which suggests that a localized neuronal-oligodendrocyte interaction may promote selective myelination by oligodendrocytes.

To verify that this activity-dependent axonal secretion of vesicles was required for maintenance of myelination by oligodendrocytes, the authors selectively reduced neuronal activity using a transgenic line with fluorescent tetanus toxin expressed in neurons (neurod1:TeNT EGFP). In this model, tetanus toxin potently inhibited neuronal activity in the fish larvae and they showed no spontaneous activity or response to touch. Oligodendrocytes formed nascent sheaths on axons in this transgenic model, but using time-lapse microscopy imaging, they observed that established sheaths were more frequently lost in the (neurod1:TeNT EGFP) transgenic line than the normal control line over a 15 hour period, supporting the idea that neuronal axon activity is important for sustained oligodendrocyte myelination of axons. In the authors’ own words, “maintenance of nascent sheaths is regulated by activity-dependent secretion from axons, whereas initial axon wrapping is activity independent”. The accompanying Figure 1 that I constructed summarizes this concept in a simple diagram that hopefully makes the idea simple to comprehend.

Figure 1. Oligodendrocytes form myelin sheaths on multiple axons in the central nervous system (CNS) during development. However, maintenance depends on activity of axons previously ensheathed by oligodendrocytes.

This study is important for a number of reasons. One, it provides an extensive analysis in an animal model that activity of axons is crucial to the maintenance, and some degree phenotype) of myelination of CNS axons by oligodendrocytes. From a purely scientific standpoint, this provides a foundation for further work in understanding oligodendrocyte developmental biology and axonal interaction mechanisms. Secondly, diseases that result in lost of oligodendrocyte myelination in the CNS, such as multiple sclerosis, are complicated and the full mechanisms of disease onset, progression, and remission remain unclear. This study may shed light on why some subsets of axonal tracts are affected as they are, whereas they seem somewhat random based on our current understanding of the disease. Perhaps there is some specific localized axonal dysfunction that cues local oligodendrocytes to demyelinate, causing signal transduction problems and symptomatic onset in MS patients.  This is all speculation, but such research opens doors for asking questions such as this to bridge basic research for the application of knowledge to the understanding and treatment of human disease.

Jacob H Hines, Andrew M Ravanelli, Rani Schwindt, Ethan K Scott & Bruce Appel (2015) _Neuronal activity biases axon selection for myelination in vivo_. Nature Neuroscience, doi:10.1038/nn.3992.