Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors.

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Gautier, Hélène OB 
Evans, Kimberley A 
Volbracht, Katrin 
James, Rachel 
Sitnikov, Sergey 

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.

Action Potentials, Adult, Animals, Axons, Brain, Female, Glutamic Acid, Humans, Immunohistochemistry, Male, Microscopy, Electron, Middle Aged, Multiple Sclerosis, Myelin Sheath, Neurons, Oligodendroglia, Patch-Clamp Techniques, Rats, Rats, Sprague-Dawley, Receptors, AMPA, Receptors, Kainic Acid, Regeneration, Stem Cells, Vesicular Glutamate Transport Protein 2
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Nat Commun
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Springer Science and Business Media LLC
Wellcome Trust (091543/Z/10/Z)
Medical Research Council (G0701476)
European Commission (214003)
Wellcome Trust (097922/Z/11/B)
This work was supported by the Medical Research Council (R.T.K, R.J.M.F and H.O.B.G. G0701476; K.V. and R.T.K 1233560), Wellcome Trust (R.T.K. and K.A.E. 091543/Z/10/Z), Marie Curie training programme Axregen EC FP7 ITN (I.L. and R.T.K 214003), and core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute.