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.
