Microglia Ingest Myelin Sheaths During Development

Post by D. Chloe Chung

What's the science?

Myelin is an important structure in the brain that surrounds the neuronal axons and helps neurons efficiently transmit electrical signals. During the development of the central nervous system, oligodendrocytes initially produce myelin in excess which eventually gets trimmed down to an appropriate amount. While previous studies have shown that oligodendrocytes can “retract” their myelinating membranes, it is unclear whether other types of cells are also involved in removing excessive myelin sheaths. This week in Nature Neuroscience, Hughes and Appel used zebrafish models to demonstrate that microglia, a type of immune cell in the central nervous system, can actively ingest or phagocytose new myelin sheaths during normal development.

How did they do it?

The authors created a transgenic zebrafish line in which microglia and myelinating oligodendrocytes were labeled with fluorescent proteins of different colors. A few days after these zebrafish were fertilized, the authors used time-lapse imaging to monitor the interaction between microglia and oligodendrocytes during the developmental stage. They also made another zebrafish line that allows visualization of phagocytic activity of microglia via calcium imaging. To understand the dynamics among neuronal activity, microglia phagocytosis, and developmental myelin elimination, the authors genetically manipulated their zebrafish model to silence or activate a subgroup of neurons. As an additional approach, zebrafish were forced to swim against strong water currents so that their neuronal activity could be continuously increased. To evaluate the direct role of microglia in the elimination of new myelin sheaths, the authors tested multiple different methods to remove microglia in zebrafish and observed the subsequent changes in developmental myelination.

What did they find?

During live imaging of young transgenic zebrafish, the authors observed that during development, microglia actively survey dynamic myelination along axon tracts in the spinal cord. In fact, unlike previous beliefs, the authors observed that myelin sheaths that were eliminated were mostly being contacted by microglia rather than being retracted by oligodendrocytes (not associated with microglial processes). Interestingly, phagocytic microglia were found to be specifically engulfing myelin sheaths but not oligodendrocytes, leaving the majority of oligodendrocyte cell bodies intact. The authors also found an interesting link between neuronal activity and microglia-mediated removal of myelin. Upon inhibition of neuronal activity, microglia less frequently contacted the neuronal cell body while engulfing more myelin. On the contrary, when neuronal activity was increased, microglia interacted more with neuronal cell bodies and substantially decreased their phagocytic activity for myelin sheaths. These results suggest that neuronal activity can regulate the amount of phagocytosis of myelin sheaths. Importantly, excessive new myelin sheaths failed to be removed in the absence of phagocytic microglia, which further highlights the essential role of microglia in modulating myelination during development.

What’s the impact?

This study is the first one to show that phagocytic microglia are active participants in removing excessive myelin sheaths during development. These findings importantly contribute to an increasing body of literature that supports the importance of microglia not only in the context of injury or disease but also in the normal development of the central nervous system. It will be interesting for future studies to investigate specific molecular cues that can trigger microglia to engulf new myelin sheaths.

Hughes & Appel. Microglia phagocytose myelin sheaths to modify developmental myelination. Nature Neuroscience (2020). Access the original scientific publication here.