Stimulating oligodendrocytes to remyelinate across the myelinating synapse


Gautier HO, Evans KA, Volbracht K, James R, Sitnikov S, Lundgaard I, James F, Lao-Peregrin C, Reynolds R, Franklin RJ, Káradóttir RT.Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors. Nat Commun. 2015 Oct 6;6:8518. doi: 10.1038/ncomms9518

Myelin regeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms and causes of its frequent failure remain incompletely understood. Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active and generate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early after lesion induction, sense neuronal activity by expressing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. In the absence of neuronal activity there is a ∼6-fold increase in OPC number within the lesions and a reduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity and release of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recover lost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that this mechanism may provide novel targets to therapeutically enhance remyelination.

Some time ago it was found that some oligodendrocyte precursor cells, which differentitate in to myelin-forming cells, can respond to glutamate, which is the major excitatory nerve transmitter. What was this for?

In this study they demyelinated some axons by killing the local oligodendrocytes and saw that the newly recruited oligodendrocyte precursors were going to express glutamate receptors and that the nerves were signalling. They then measured the voltage of these cells and could see that they were recieving electrical signalling and they were forming the “myelinating synapse”. These currents were mediated by the AMPA type of glutamate receptors. When myelination was complete these myelinating synapses were undetectable,.

Was this cause or effect and were they involved in remyelination, so they blocked nerve signalling potential and remyelination was reduced. 

The AMPA-glutamate receptor responses were detected early and these were not responsive to NMDA glutamate receptor blockers. AMPA blockers could inhibit remyelination, they  then looked and found that NMDA glutamate receptors appear as the oligodendrocyte precurosor cells differentiate and they have shown that blocking NMDA but not AMPA glutamate receptors block remyelination

This indicates that AMPA/kainate receptor activation is essential for the early stages of remyelination, whereas NMDA receptors are important for later stages of remyelination.

It was found that neural activity was needed for remyelination and there axonal oligodendrocyte cross talk by the injured nerve promotes repair. This looks like how nerves myelinate in early development and direct OPC differentiation by maintaining electrical activity ence, it is conceivable that the use of agonists that promote impulse propagation, vesicular release and/or AMPA receptor currents in OPCs may promote OPC differentiation and myelin repair in disease. 

However it also shows us that nature can use the same pathways to do many different things and these may be complementary, but they may also be antagonistic. 

Long-term agonism of these pathways will probably be bad news.

AMPA receptor antagonists have be shown to have symptom modifying potential and can inhibit excitotoxicity and could have the potential to be neuroprotective. A number of companies were investigating these in MS and they have not surfaced as being useful. 

Is it because they blocked remyelination and made things worse? or is it because these molecules are toxic as hell and induced all sorts of problems. at too high a does they kill animals, at lower doses they sedate animals. They also desensitize the system so the things don’t work any more. Anything that is a strong antagonist is dangerous to these ionotrophic (stimulates ionic movements in to and out of cells for signalling) glutamate receptors in my humble opinion.

Likewise NMDA antagonists have been used in MS and again they have resulted in mixed results. Memantine is a weak blocker and is used in Altzheimers to slow loss of cognitive function. 

However, it didn’t work in some trials in MS. Is it because it limits remyelination?. However, in other cases memantine inhibits sypmtoms of MS and is clearly neuroprotective in animals, so going on the other side of the equation could be be neurodestructive. 

So now GABA is on the other side of neural signalling and counteracts the effect of glutamate. It is used as a symptom control drug, but has recently been suggested to neuroprotective. Does this inhibit or augment myelination. The answer is we don’t know but shows that when you use agents they are often a balance of positive verses negative effects.

Never the less a nice piece of work that tells us more about how to remyelinate and it could lead to avenues for repair.

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  • This line of research floats my boat, I like Gregoire Courtine's work and maybe some sort of jump start going on ?

    Regards as always.

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