Signalling through AMPA receptors on oligodendrocyte precursors promotes myelination by enhancing oligodendrocyte survival

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Abstract

Myelin, made by oligodendrocytes, is essential for rapid information transfer in the central nervous system. Oligodendrocyte precursors (OPs) receive glutamatergic synaptic input from axons but how this affects their development is unclear. Murine OPs in white matter express AMPA receptor (AMPAR) subunits GluA2, GluA3 and GluA4. We generated mice in which OPs lack both GluA2 and GluA3, or all three subunits GluA2/3/4, which respectively reduced or abolished AMPAR-mediated input to OPs. In both double- and triple-knockouts OP proliferation and number were unchanged but ~25% fewer oligodendrocytes survived in the subcortical white matter during development. In triple knockouts, this shortfall persisted into adulthood. The oligodendrocyte deficit resulted in ~20% fewer myelin sheaths but the average length, number and thickness of myelin internodes made by individual oligodendrocytes appeared normal. Thus, AMPAR-mediated signalling from active axons stimulates myelin production in developing white matter by enhancing oligodendrocyte survival, without influencing myelin synthesis per se.

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Eleni Kougioumtzidou

Wolfson Institute for Biomedical Research, University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Takahiro Shimizu

Wolfson Institute for Biomedical Research, University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Nicola B Hamilton

Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Koujiro Tohyama

The Center for Electron Microscopy and Bio-Imaging Research, Iwate Medical University, Morioka, Japan

Competing interests
The authors declare that no competing interests exist.
Rolf Sprengel

Institute for Anatomy and Cell Biology, University of Heidelberg, Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.
Hannah Monyer

Department of Clinical Neurobiology, University of Heidelberg, Heidelberg, Germany

Competing interests
The authors declare that no competing interests exist.
David Attwell

Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

For correspondence
d.attwell@ucl.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3618-0843
William D Richardson

Wolfson Institute for Biomedical Research, University College London, London, United Kingdom

For correspondence
w.richardson@ucl.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7261-2485

Funding

Wellcome (100269/Z/12/Z)

William D Richardson

Japan Society for the Promotion of Science (24650181)

Koujiro Tohyama

Wellcome (108726/Z/15/Z)

William D Richardson

Wellcome (099222/Z/12/Z)

David Attwell

Wellcome (089591/Z/09/Z)

Eleni Kougioumtzidou

European Research Council (293544)

William D Richardson

German Research Foundation (SFB636/A4)

Rolf Sprengel

German Research Foundation (SFB1134/B01)

Rolf Sprengel

German Research Foundation (SFB 1158/A05)

Rolf Sprengel

Japan Society for the Promotion of Science (25245069)

Koujiro Tohyama

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were pre-approved by the UCL Ethical Committee and authorized by the Home Office of the UK Government in accordance with Animals (Scientific Procedures) Act 1986., under Project Licences PPL 70/7299 and PPL 70/8976 (D. Attwell) and PPL 70/7614 (W.D. Richardson).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.