Axonal Selectivity of Myelination by Single Oligodendrocytes Established During Development in Mouse Cerebellar White Matter

ABSTRACT Myelin formation by oligodendrocytes regulates the conduction velocity and functional integrity of neuronal axons. While individual oligodendrocytes form myelin sheaths around multiple axons and control the functions of neural circuits where the axons are involved, it remains unclear if oligodendrocytes selectively form myelin sheaths around specific subtypes of axons. Using the combination of rabies virus‐mediated single oligodendrocyte labeling and immunostaining with tissue clearing, we revealed that approximately half of the oligodendrocytes preferentially myelinate axons originating from Purkinje cells in the white matter of adult mouse cerebella. The preference for Purkinje cell axons was more pronounced during development when the process of myelination within cerebellar white matter was initiated; over 90% of oligodendrocytes preferentially myelinated Purkinje cell axons. Preferential myelination of Purkinje cell axons was further confirmed by immuno‐electron microscopy and transgenic mice that label early‐born oligodendrocytes. Transgenic mice that label oligodendrocytes differentiated at the early development showed that early‐born oligodendrocytes preferentially myelinate Purkinje cell axons in the matured cerebellar white matter. In contrast, transgenic mice that label oligodendrocytes differentiated after the peak of cerebellar myelination showed that the later‐differentiated oligodendrocytes dominantly myelinated non‐Purkinje cell axons. These results demonstrate that a significant proportion of oligodendrocytes preferentially myelinate functionally distinct axons in the cerebellar white matter, and the axonal preference of myelination by individual oligodendrocytes is established depending on the timing of their differentiation during development. Our data provide the evidence that there is a critical time window of myelination that a specific subtype of axons are dominantly myelinated by the oligodendrocytes.