OLIGODENDROCYTE HCN2 CHANNELS REGULATE MYELIN SHEATH LENGTH

Abstract

Oligodendrocytes generate myelin sheaths vital for the formation, health and function of the central nervous system (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 recognised 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 hyperpolarisation-activated, cyclic nucleotide-gated (HCN) 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 channels. These HCN 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 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 signalling mechanisms responsible for determining sheath length are poorly understood. Here we find that oligodendrocytes express functional hyperpolarisation-activated, cyclic nucleotide-gated (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 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.