Abstract
SummaryMyelination of axons by oligodendrocytes enables fast saltatory conduction. Oligodendrocytes are responsive to neuronal activity, which has been shown to induce changes to myelin sheaths, potentially to optimize conduction and neural circuit function. However, the cellular bases of activity-regulated myelination in vivo are unclear, partly due to the difficulty of analyzing individual myelinated axons over time. Activity-regulated myelination occurs in specific neuronal subtypes and can be mediated by synaptic vesicle fusion, but several questions remain: it is unclear whether vesicular fusion occurs stochastically along axons or in discrete hotspots during myelination and whether vesicular fusion regulates myelin targeting, formation, and/or growth. It is also unclear why some neurons, but not others, exhibit activity-regulated myelination. Here, we imaged synaptic vesicle fusion in individual neurons in living zebrafish and documented robust vesicular fusion along axons during myelination. Surprisingly, we found that axonal vesicular fusion increased upon and required myelination. We found that axonal vesicular fusion was enriched in hotspots, namely the heminodal non-myelinated domains into which sheaths grew. Blocking vesicular fusion reduced the stable formation and growth of myelin sheaths, and chemogenetically stimulating neuronal activity promoted sheath growth. Finally, we observed high levels of axonal vesicular fusion only in neuronal subtypes that exhibit activity-regulated myelination. Our results identify a novel “feedforward” mechanism whereby the process of myelination promotes the neuronal activity-regulated signal, vesicular fusion that, in turn, consolidates sheath growth along specific axons selected for myelination.
Highlights
It is unclear whether synaptic vesicle fusion along the axon precedes and biases myelin targeting to more active axons or only consolidates myelin sheaths after their formation
Our results identify a novel feedforward mechanism whereby the process of myelination promotes the neuronal activity-regulated signal, vesicular fusion that, in turn, stimulates sheath formation and growth along specific axons selected for myelination
Synaptic vesicle fusion occurs along reticulospinal axons To elucidate the mechanisms by which synaptic vesicle fusion and neuronal activity regulate myelination in intact neural circuits, we first aimed to define when and where synaptic vesicles fuse along axons
Summary
Ensheathment of axons by myelin drastically changes their conduction properties, enabling fast saltatory conduction of action potentials[1] and providing axons with metabolic support.[2,3,4] Dynamic changes to axonal myelination occur throughout life[5] (e.g., through the differentiation of oligodendrocytes that form new myelin sheaths along previously unmyelinated or partially myelinated axons) or through remodeling of existing myelin sheaths.[6,7] Oligodendrocytes express numerous neurotransmitters receptors and are responsive to neuronal activity.[8,9,10] optogenetic or chemogenetic stimulation of neuronal firing can promote myelination along manipulated axons in vivo.[11,12] experiencedependent changes in myelination induced by neuronal activity are increasingly implicated in numerous aspects of nervous system formation, function, and health.[13,14,15,16] the cellular bases for how neuronal activity along axons might regulate myelination in vivo are unclear. Recent studies suggested that the effects of neuronal activity on myelination are mediated by the release of synaptic vesicles,[17,18] including in a neuron-subtype-specific manner.[19,20] For example, in zebrafish, blocking vesicular fusion from specific neurons reduced myelin sheath number and length along their axons.[18,20] live-imaging studies revealed that synaptic vesicles can accumulate along axons during myelination,[18,21,22] leading to the model that vesicular cargo directly drives myelin sheath formation and/or growth.[23] it is unclear whether synaptic vesicle fusion along the axon precedes and biases myelin targeting to more active axons or only consolidates myelin sheaths after their formation.
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