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Oligodendrocyte hcn2 channels regulate myelin sheath length

Research output: Contribution to journalArticlepeer-review

Matthew Swire, Peggy Assinck, Peter A. McNaughton, David A. Lyons, Charles Ffrench-Constant, Matthew R. Livesey

Original languageEnglish
Pages (from-to)7954-7964
Number of pages11
JournalJournal of Neuroscience
Volume41
Issue number38
DOIs
Published22 Sep 2021

Bibliographical note

Funding Information: This work was supported by a Wellcome Trust Senior Investigator Award to C.f-C., a Wellcome Trust Senior Research Fellowship award (214244/Z/18/Z) to D.A.L. and a Royal Society of P.A. holds a Marie Curie Individual Fellowship. We thank past and present members of the ffrench-Constant and Lyons laboratories for assistance and discussions. We also thank Dr. Sam Booker for helpful discussions on electrophysiological recordings. In addition, we thank Professor William Richardson for the use of reagents and facilities. Finally, we thank the University of Edinburgh for animal husbandry and support facilities. The authors declare no competing financial interests. Publisher Copyright: © 2021 Society for Neuroscience. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Oligodendrocytes generate myelin sheaths vital for the formation, health, and function of the CNS. Myelin sheath length is a key property that determines axonal conduction velocity and is known to be variable across the CNS. Myelin sheath length can be modified by neuronal activity, suggesting that dynamic regulation of sheath length might contribute to the functional plasticity of neural circuits. Although the mechanisms that establish and refine myelin sheath length are important determinants of brain function, our understanding of these remains limited. In recent years, the membranes of myelin sheaths have been increasingly recognized to contain ion channels and transporters that are associated with specific important oligodendrocyte functions, including metabolic support of axons and the regulation of ion homeostasis, but none have been shown to influence sheath architecture. In this study, we determined that hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels, typically associated with neuronal and cardiac excitability, regulate myelin sheath length. Using both in vivo and in vitro approaches, we show that oligodendrocytes abundantly express functional, predominantly HCN2 subunit-containing ion channels. These HCN ion channels retain key pharmacological and biophysical features and regulate the resting membrane potential of myelinating oligodendrocytes. Further, reduction of their function via pharmacological blockade or generation of transgenic mice with two independent oligodendrocyte-specific HCN2 knock-out strategies reduced myelin sheath length. We conclude that HCN2 ion channels are key determinants of myelin sheath length in the CNS.

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