During development, oligodendrocytes contact and wrap neuronal axons with myelin. Similar to neurons and synapses, excess myelin sheaths are produced and selectively eliminated. However, unlike these other structures, almost nothing is known about myelin sheath elimination. Microglia, the resident immune cells of the CNS, refine the developing CNS by engulfing surplus neurons and synapses. To determine if microglia also prune myelin sheaths, we used zebrafish to visualize and manipulate interactions between microglia, oligodendrocytes, and neurons during development. We found that microglia closely associate with oligodendrocytes and specifically phagocytose myelin sheaths. Silencing neuronal activity with botulinum toxin (BoNT/B) increased myelin engulfment by microglia. Furthermore, oligodendrocytes maintained excessive myelin sheaths following microglial ablation. Our work reveals a neuronal activity-regulated role for microglia in regulating myelination by oligodendrocytes.
Main Text:Neuronal axon conduction velocity is supported by myelin, a specialized, proteolipid-rich membrane. During development, oligodendroglial cells, or oligodendrocytes, generate numerous nascent myelin sheaths along axons. Neuronal activity promotes the formation and maturation of myelin sheaths (1-6), processes that are mechanistically reminiscent to synaptogenesis (7). Like synapses, myelin sheaths are pruned after formation (8). However, we know almost nothing about the mechanisms that underlie myelin pruning. Synapses in the developing CNS can be pruned by microglia, the resident immune cells of the CNS. Microglia locate and engulf weak synapses in an activity-regulated manner, leaving stronger synapses intact (9). Could microglia also prune myelin sheaths to refine myelination?To visualize microglia, we established a transgenic line of zebrafish, Tg(mpeg1.