Oligodendrocytes form paranodal bridges that generate chains of myelin sheaths vulnerable to degeneration with age

Abstract

Myelin sheaths in the CNS are generated by the tips of oligodendrocyte processes, which wrap axons to accelerate action potential conduction, provide metabolic support and control excitability. Here we identify a distinct mode of myelination, conserved between zebrafish, mouse and human, in which oligodendrocytes extend myelin along individual axons by linking myelin sheaths across nodes of Ranvier (NoR). By forming thin extensions that cross NoR, which we term paranodal bridges, multiple sheaths can be connected to the soma by a single cytoplasmic process. Extensive in vivo live imaging-based analyses, complemented by serial electron microscopic reconstruction of paranodal bridges, revealed that many oligodendrocytes use this strategy to generate longer stretches of myelin along individual axons. In the mouse somatosensory cortex, paranodal bridges were particularly prevalent along the highly branched axons of parvalbumin expressing (PV) interneurons, which enabled oligodendrocytes to extend myelin sheaths around axon bifurcations. Sheaths at the distal ends of these chains of myelin degenerated more frequently in aged mice, suggesting that they may be more vulnerable to the aging brain environment. This previously undescribed and evolutionarily conserved feature of oligodendrocytes extends myelin coverage of individual axons without new oligodendrogenesis, which may reduce metabolic demand and preserve the fidelity of action potential propagation at axon branch points.