Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length

The Journal of Neuroscience, 2021 · DOI: https://doi.org/10.1523/JNEUROSCI.2463-20.2021 · Published: September 22, 2021

Simple Explanation

Myelin sheath length, which affects how fast signals travel in the brain, can change, suggesting it helps the brain adapt. While we know myelin sheaths contain ion channels important for cell function, we don't know if these channels affect sheath structure. This study finds that HCN channels, usually found in neurons and heart cells, are also in oligodendrocytes and control myelin sheath length. Using lab experiments and modified mice, researchers showed oligodendrocytes have working HCN2 channels. These channels control the cell's resting state. When the researchers blocked these channels or removed them in mice, the myelin sheaths became shorter. This suggests that HCN2 channels determine how long myelin sheaths are in the brain. The study suggests HCN2 channels might link myelin sheath structure to signals from axons, like those from increased activity. These channels could change myelin structure based on these signals, offering a way for the brain to adapt and refine how it works.

Study Duration

Not specified

Participants

Mice

Evidence Level

In vivo and in vitro approaches

Key Findings

1
Oligodendrocytes abundantly express functional, predominantly HCN2 subunit-containing ion channels, which retain key pharmacological and biophysical features.
2
HCN2 ion channels regulate the resting membrane potential of myelinating oligodendrocytes.
3
Reduction of HCN2 function via pharmacological blockade or genetic knockout reduced myelin sheath length.

Research Summary

This study investigates the role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels in oligodendrocytes, focusing on their impact on myelin sheath length. The researchers found that oligodendrocytes express functional HCN2 channels that regulate the cell's resting membrane potential and are essential for maintaining normal myelin sheath length. Both in vitro and in vivo experiments demonstrated that reducing HCN2 channel function leads to shorter myelin sheaths, indicating a crucial role in myelin sheath elongation and suggesting a potential mechanism for adaptive myelination.

Practical Implications

Therapeutic potential

Modulating HCN2 channel activity could be a target for therapies aimed at refining myelin sheath length and improving axonal conduction in demyelinating diseases.

Adaptive Myelination

The discovery provides a potential mechanism for receptors responding to the release of neurotransmitter from active axons to alter HCN2 activity via intracellular signaling mechanisms and so to mediate localized changes in Ca21 activity that regulate sheath growth.

Understanding circuit function

Further research is needed to explore the significance of HCN2 ion channel regulation of sheath length for circuit function in the CNS, which may involve morphologic, electrophysiological, and behavioral analyses of the cKO mice.

Study Limitations

1
The study did not distinguish whether the minority of oligodendrocytes not expressing HCN2 resulted from distinct populations of permanently HCN2-positive or HCN2-negative cells, or as a result of HCN2 only being expressed at specific stages of oligodendrocyte maturation.
2
The precise mechanisms by which HCN2 channels regulate myelin sheath elongation remain to be fully elucidated.
3
Further studies are required to determine the specific axonal signals that modulate HCN2 activity and how these signals are translated into changes in myelin sheath growth.

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