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Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors

Gautier, Hélène O.B. ; Evans, Kimberley A. ; Volbracht, Katrin ; James, Rachel ; Sitnikov, Sergey ; Lundgaard, Iben LU ; James, Fiona ; Lao-Peregrin, Cristina ; Reynolds, Richard and Franklin, Robin J.M. , et al. (2015) In Nature Communications 6.
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 â1/46-fold increase in... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
6
article number
8518
publisher
Nature Publishing Group
external identifiers
  • scopus:84943339561
  • pmid:26439639
ISSN
2041-1723
DOI
10.1038/ncomms9518
language
English
LU publication?
no
id
14830fcb-50e6-488b-985d-bcb5441ddbf5
date added to LUP
2019-05-16 16:43:10
date last changed
2024-06-26 16:12:39
@article{14830fcb-50e6-488b-985d-bcb5441ddbf5,
  abstract     = {{<p>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.</p>}},
  author       = {{Gautier, Hélène O.B. and Evans, Kimberley A. and Volbracht, Katrin and James, Rachel and Sitnikov, Sergey and Lundgaard, Iben and James, Fiona and Lao-Peregrin, Cristina and Reynolds, Richard and Franklin, Robin J.M. and Káradóttir, Ragnhildur T.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{10}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors}},
  url          = {{http://dx.doi.org/10.1038/ncomms9518}},
  doi          = {{10.1038/ncomms9518}},
  volume       = {{6}},
  year         = {{2015}},
}