Precision in a sea of profusion: Myelin replacement triggered by single-cell cortical demyelination

Abstract

Myelin--rather than being a static insulator of axons--is emerging as an active participant in circuit plasticity. This requires precise regulation of oligodendrocyte numbers and myelination patterns. Here, by devising a laser ablation approach of single oligodendrocytes, followed by in vivo imaging and correlated ultrastructural reconstruction, we show that in mouse cortex demyelination as subtle as loss of a single oligodendrocyte can trigger robust cell replacement and remyelination timed by myelin breakdown. This results in reliable reestablishment of the original myelin pattern along continuously myelinated axons, while in parallel profuse isolated internodes emerge on previously unmyelinated axons. Thus, in mammalian cortex, internodes along partially myelinated cortical axons are typically not re-established, suggesting that the cues that guide patchy myelination are not preserved through cycles of de- and remyelination. In contrast, continuous obligatory myelin shows remarkable homeostatic resilience with single axon precision.