Oligodendrocyte hcn2 channels regulate myelin sheath length

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

doi:10.1523/JNEUROSCI.2463-20.2021

Oligodendrocyte hcn2 channels regulate myelin sheath length

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

^*Corresponding author for this work

Wolfson SPaRC

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

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.

Original language	English
Pages (from-to)	7954-7964
Number of pages	11
Journal	Journal of Neuroscience
Volume	41
Issue number	38
DOIs	https://doi.org/10.1523/JNEUROSCI.2463-20.2021
Publication status	Published - 22 Sept 2021

Keywords

HCN
Myelin
Myelination
Oligodendrocyte
Physiology
Sheath

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10.1523/JNEUROSCI.2463-20.2021

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title = "Oligodendrocyte hcn2 channels regulate myelin sheath length",

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.",

keywords = "HCN, Myelin, Myelination, Oligodendrocyte, Physiology, Sheath",

author = "Matthew Swire and Peggy Assinck and McNaughton, {Peter A.} and Lyons, {David A.} and Charles Ffrench-Constant and Livesey, {Matthew R.}",

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: {\textcopyright} 2021 Society for Neuroscience. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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doi = "10.1523/JNEUROSCI.2463-20.2021",

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AU - Swire, Matthew

AU - Assinck, Peggy

AU - McNaughton, Peter A.

AU - Lyons, David A.

AU - Ffrench-Constant, Charles

AU - Livesey, Matthew R.

N1 - 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.

PY - 2021/9/22

Y1 - 2021/9/22

N2 - 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.

AB - 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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KW - Myelin

KW - Myelination

KW - Oligodendrocyte

KW - Physiology

KW - Sheath

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SN - 0270-6474

VL - 41

SP - 7954

EP - 7964

JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 38

ER -

Oligodendrocyte hcn2 channels regulate myelin sheath length

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