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 â1/46-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.
We thank William Stallcup for NG2 antibody; Jacqueline Trotter for NG2-EYFP knock-in mice; Mike Peacock and Daniel Morrison for electron microscope imaging assistance; Peter Humphreys for confocal imaging assistance and assistance with Iso-surface 3D deconvolution; John Brown and Helen Skelton for histology assistance; Kathrin Holtzmann, Claire Custance and Sally Ashworth for assistance during surgeries; and Kristian Franze and Jeffrey Huang for critical comments on the manuscript. Human postmortem tissues were supplied by the MS Society Tissue Bank (funded by the Multiple Sclerosis Society, registered charity 207495, R.R.). 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), MS Society (R.T.K. and R.J.M.F.), 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.
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