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.SIGNIFICANCE STATEMENT Myelin sheath length is a critical determinant of axonal conduction velocity, but the signaling mechanisms responsible for determining sheath length are poorly understood. Here we find that oligodendrocytes express functional hyperpolarization-activated, cyclic nucleotide-gated 2 (HCN2) ion channels that regulate the length of myelin sheaths formed by oligodendrocytes in myelinating cultures and in the mouse brain and spinal cord. These results suggest that the regulation of HCN2 channel activity is well placed to refine sheath length and conduction along myelinated axons, providing a potential mechanism for alterations in conduction velocity and circuit function in response to axonal signals such as those generated by increased activity.
Highlights
Myelin sheaths accelerate axonal action potential conduction velocity through the establishment of saltatory conduction (Huxley and Stampfli, 1949; Rushton, 1951; Waxman, 1997; Cohen et al, 2020)
We examined the localization of HCN2 protein in vivo, identifying robust expression within oligodendrocyte cell bodies and diffuse staining throughout myelin sheaths (Fig. 1D)
The maturation of oligodendrocyte progenitors to myelinating oligodendrocytes involves major changes in membrane physiology, ion channel composition, and generation of distinct biophysical membrane properties (Káradóttir and Attwell, 2007; Bakiri et al, 2009; Larson et al, 2016). As part of these changes, functional HCN2 ion channels become expressed in myelinating oligodendrocytes
Summary
Myelin sheaths accelerate axonal action potential conduction velocity through the establishment of saltatory conduction (Huxley and Stampfli, 1949; Rushton, 1951; Waxman, 1997; Cohen et al, 2020). J. Neurosci., September 22, 2021 41(38):7954–7964 7955 populations express a number of ion channels, transporters, and receptors with currently undefined roles (Zhang et al, 2014; Marques et al, 2016; Thakurela et al, 2016; Suminaite et al, 2019). Neurosci., September 22, 2021 41(38):7954–7964 7955 populations express a number of ion channels, transporters, and receptors with currently undefined roles (Zhang et al, 2014; Marques et al, 2016; Thakurela et al, 2016; Suminaite et al, 2019) Such studies have identified that oligodendrocytes express hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels. Given that HCN ion channels are known for regulating basal neuronal and cardiac membrane excitability through their hyperpolarizationactivated depolarizing currents (Biel et al, 2009) and that oligodendrocytes have a hyperpolarized resting membrane potential (RMP; Larson et al, 2016), we reasoned that HCN ion channels might play a physiological role in oligodendrocytes
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