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The Neuroscientist Comments

One of the many remarkable features of the CNS is the presence of myelin – high-resistance, low-capacitance insulation – around certain axons, an architectural feature that allows them to conduct impulses rapidly without the cost of an increase in diameter and a consequent increase in brain size. It is well-established that myelination tends to occur after axons reach a critical size, but we still only partially understand the conversation between axons and myelin-forming oligodendrocytes that results in the formation of stable, compact myelin. Numerous studies have suggested that electrical activity along axons plays a role in promoting myelination, but the mechanisms that direct myelination in vivo have remained enigmatic. Now, Hines and others (2015) report an interesting study using zebrafish, in which they observe that activity-dependent secretion stabilizes myelin sheath formation along specific axons. Using transgenic reporters that allow direct observation of subsets of myelinfated axons together with drivers that enabled genetic manipulation of neuronal activity, they report that tetrodotoxin (TTX)-sensitive axonal activity is not a prerequisite for oligodendrocyte differentiation or formation of nascent myelin in vivo, but that it biases the choice of axons to be myelinated. Conversely, their observations suggest that TTX-sensitive activity is a prerequisite for selection of specific axons at high fidelity although wide-spread elevated neuronal activity is not sufficient, in itself, to increase ensheathment of spinal cord axons. Building upon these observations, they inhibited synaptic vesicle exocytosis in a subgroup of axons via a strategy that targeted VaMP2 and showed that when VaMP2exocytosis was blocked in single axons, oligodendrocytes preferentially ensheathed neighboring nerve fibers. Hypothesizing that vesicle release from axons regulates selection from myelination, they used confocal microscopy to demonstrate that intraaxonal vesicles tend to be stationary at sites of ensheathment, an observation that supports the possibility that axon secretion participates in the selection of axons for ensheathment. Using time-lapse microscopy, they then observed that the majority of initially wrapping oligodendrocyte segments failed to form stable sheaths, an observation that they interpret as showing that activity-dependent secretion biases the formation of stable myelin sheaths. They propose a model in which axon selection for myelination involves indiscriminate, excessive initiation of wrapping which is followed by the formation of stable myelin sheaths along a subset of axons, biased by activity-dependent axonal secretion. The precise nature of the secreted molecules, which act as messengers that regulate the formation of stable myelin sheaths, remains to be determined.