title: Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors.
abstract: 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.
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Hélène O B
authors.initials: HO
authors.lastname: Gautier
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Evans
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Volbracht
authors.affiliation: Faculty of Medicine, Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: James
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Sergey
authors.initials: S
authors.lastname: Sitnikov
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Iben
authors.initials: I
authors.lastname: Lundgaard
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: James
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lao-Peregrin
authors.affiliation: Faculty of Medicine, Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0AH, UK.
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.affiliation: Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Ragnhildur T
authors.initials: RT
authors.lastname: Káradóttir
mesh_terms: D000200:Action Potentials; D000328:Adult; D000818:Animals; D001369:Axons / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D013234:Stem Cells; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: D018698:Glutamic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D050599:Vesicular Glutamate Transport Protein 2; C493476:SLC17A6 protein, human