The myelination of axons by oligodendrocytes profoundly affects central nervous system function, but how this is regulated by neuronal activity in vivo is not known. Here we find that blocking synaptic vesicle release impairs CNS myelination by reducing the number of myelin sheaths made by individual oligodendrocytes during their short period of formation. We also find that stimulating neuronal activity increases myelin sheath formation by individual oligodendrocytes. These data show that neuronal activity regulates the myelinating capacity of single oligodendrocytes.

SummaryRegulation of myelination by oligodendrocytes in the CNS has important consequences for higher-order nervous system function (e.g., [1, 2, 3, 4]), and there is growing consensus that neuronal activity regulates CNS myelination (e.g., [5, 6, 7, 8, 9]) through local axon-oligodendrocyte synaptic-vesicle-release-mediated signaling [10, 11, 12]. Recent analyses have indicated that myelination along axons of distinct neuronal subtypes can differ [13, 14], but it is not known whether regulation of myelination by activity is common to all neuronal subtypes or only some. This limits insight into how specific neurons regulate their own conduction. Here, we use a novel fluorescent fusion protein reporter to study myelination along the axons of distinct neuronal subtypes over time in zebrafish. We find that the axons of reticulospinal and commissural primary ascending (CoPA) neurons are among the first myelinated in the zebrafish CNS. To investigate how activity regulates myelination by different neuronal subtypes, we express tetanus toxin (TeNT) in individual reticulospinal or CoPA neurons to prevent synaptic vesicle release. We find that the axons of individual tetanus toxin expressing reticulospinal neurons have fewer myelin sheaths than controls and that their myelin sheaths are 50% shorter than controls. In stark contrast, myelination along tetanus-toxin-expressing CoPA neuron axons is entirely normal. These results indicate that while some neuronal subtypes modulate myelination by synaptic vesicle release to a striking degree in vivo, others do not. These data have implications for our understanding of how different neurons regulate myelination and thus their own function within specific neuronal circuits.

During myelination, individual oligodendrocytes initially over-produce short myelin sheaths that are either retracted or stabilised. By live imaging oligodendrocyte Ca2+ activity in vivo, we find that high-amplitude long-duration Ca2+ transients in sheaths prefigure retractions, mediated by calpain. Following stabilisation, myelin sheaths grow along axons, and we find that higher frequency Ca2+ transient activity in sheaths precedes faster elongation. Our data implicate local Ca2+ signalling in regulating distinct stages of myelination.

Myelinated axons with nodes of Ranvier are an evolutionary elaboration common to essentially all jawed vertebrates. Myelin made by Schwann cells in our peripheral nervous system and oligodendrocytes in our central nervous system has been long known to facilitate rapid energy efficient nerve impulse propagation. However, it is now also clear, particularly in the central nervous system, that myelin is not a simple static insulator but that it is dynamically regulated throughout development and life. New myelin sheaths can be made by newly differentiating oligodendrocytes, and mature myelin sheaths can be stimulated to grow again in the adult. Furthermore, numerous studies in models from fish to man indicate that neuronal activity can affect distinct stages of oligodendrocyte development and the process of myelination itself. This begs questions as to how these effects of activity are mediated at a cellular and molecular level and whether activity-driven adaptive myelination is a feature common to all myelinated axons, or indeed all oligodendrocytes, or is specific to cells or circuits with particular functions. Here we review the recent literature on this topic, elaborate on the key outstanding questions in the field, and look forward to future studies that incorporate investigations in systems from fish to man that will provide further insight into this fundamental aspect of nervous system plasticity.This article is part of a Special Issue entitled SI: Myelin Evolution.