Myelin replacement triggered by single-cell demyelination in mouse cortex

Nicolas Snaidero,Thomas Misgeld,Aleksandra Mezydlo,Martin Kerschensteiner,Bernard Zalc,Martina Schifferer

doi:10.1038/s41467-020-18632-0

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 reconstructions, we report that in mouse cortex demyelination as subtle as the 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, patchy isolated internodes emerge on previously unmyelinated axons. Therefore, in mammalian cortex, internodes along partially myelinated cortical axons are typically not reestablished, suggesting that the cues that guide patchy myelination are not preserved through cycles of de- and remyelination. In contrast, myelin sheaths forming continuous patterns show remarkable homeostatic resilience and remyelinate with single axon precision.

Highlights

Myelin, rather than being a static insulator of axons, is emerging as an active participant in circuit plasticity
We show that the loss of a single cortical OL triggers a remarkable local response during which newly matured OLs replace the original cell in a homeostatic fashion
In the Plp:GFP transgenic line, due to the presence of the PLP peptide signal in the construct upstream of the green fluorescent protein (GFP) coding sequence, the reporter is inserted in the myelin sheath[42]

Summary

Introduction

Rather than being a static insulator of axons, is emerging as an active participant in circuit plasticity. By devising a laser ablation approach of single oligodendrocytes, followed by in vivo imaging and correlated ultrastructural reconstructions, we report that in mouse cortex demyelination as subtle as the 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, patchy isolated internodes emerge on previously unmyelinated axons. Structural changes in white matter have been associated with task learning in the adult brain[7,8,9], and such learning processes require active myelination, as well as oligodendrocyte precursor cell (OPC) proliferation and differentiation[10,11,12,13,14] Central to this new paradigm of adaptive myelin plasticity is the unique myelination pattern described in mammalian gray matter including the cortex. Understanding this is important in the context of demyelinating diseases like multiple sclerosis, where extensive cortical demyelination is emerging as a major pathological feature and a central target of remyelination therapies[32,33,34,35,36,37,38]

Methods

Results

Conclusion