Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length.
Oligodendrocyte HCN2 Channels Regulate Myelin Sheath Length.
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DOI：
10.1523/jneurosci.2463-20.2021
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发表时间：
2021-09-22
期刊：
影响因子：
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通讯作者：
Livesey MR
中科院分区：
文献类型：
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作者：
Swire M;Assinck P;McNaughton PA;Lyons DA;Ffrench-Constant C;Livesey MR
少突胶质细胞产生对于中枢神经系统的形成、健康和功能至关重要的髓鞘。髓鞘长度是决定轴突传导速度的关键特性，并且已知在中枢神经系统中是可变的。髓鞘长度可以通过神经元活动来改变，这表明髓鞘长度的动态调节可能有助于神经回路的功能可塑性。尽管建立和完善髓鞘长度的机制是大脑功能的重要决定因素，但我们对这些机制的理解仍然有限。近年来，人们越来越认识到髓鞘膜含有与特定重要少突胶质细胞功能相关的离子通道和转运蛋白，包括轴突的代谢支持和离子稳态的调节，但没有证据表明它们会影响髓鞘结构。在这项研究中，我们确定超极化激活的环核苷酸门控 (HCN) 离子通道（通常与神经元和心脏兴奋性相关）调节髓鞘长度。通过体内和体外方法，我们发现少突胶质细胞大量表达功能性离子通道，主要是含有 HCN2 亚基的离子通道。这些 HCN 离子通道保留了关键的药理学和生物物理特征，并调节有髓鞘少突胶质细胞的静息膜电位。此外，通过药理学阻断或产生具有两种独立的少突胶质细胞特异性 HCN2 敲除策略的转基因小鼠来减少其功能，可减少髓鞘长度。我们得出结论，HCN2 离子通道是中枢神经系统髓鞘长度的关键决定因素。意义声明 髓鞘长度是轴突传导速度的关键决定因素，但对决定髓鞘长度的信号传导机制知之甚少。在这里，我们发现少突胶质细胞表达功能性超极化激活的环核苷酸门控2（HCN2）离子通道，该通道调节髓鞘形成培养物以及小鼠大脑和脊髓中少突胶质细胞形成的髓鞘的长度。这些结果表明，HCN2通道活性的调节可以很好地改善鞘长度和沿有髓轴突的传导，为响应轴突信号（例如由活动增加产生的信号）改变传导速度和电路功能提供潜在机制。
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.