Experience-related reductions of myelin and axon diameter in adulthood.

The production of new myelin has been highlighted as an underappreciated mechanism of brain plasticity, but whether plastic decreases in myelin also happen in the adult brain has been largely unexplored. Recently, Sinclair et al. (Sinclair JS, Fischl MJ, Alexandrova O, Heß M, Grothe B, Leibold C, and Kopp-Scheinpflug C. J Neurosci 37: 8239-8255, 2017) have shown that auditory deprivation can lead to decrease in myelination and axon caliber even in healthy adulthood. These findings show that activity-regulated myelination is more complex than previously thought and expand our knowledge of how adult brain plasticity could operate on a cellular level.

Oligodendrocyte Neurofascin Independently Regulates Both Myelin Targeting and Sheath Growth in the CNS.

Selection of the correct targets for myelination and regulation of myelin sheath growth are essential for central nervous system (CNS) formation and function. Through a genetic screen in zebrafish and complementary analyses in mice, we find that loss of oligodendrocyte Neurofascin leads to mistargeting of myelin to cell bodies, without affecting targeting to axons. In addition, loss of Neurofascin reduces CNS myelination by impairing myelin sheath growth. Time-lapse imaging reveals that the distinct myelinating processes of individual oligodendrocytes can engage in target selection and sheath growth at the same time and that Neurofascin concomitantly regulates targeting and growth. Disruption to Caspr, the neuronal binding partner of oligodendrocyte Neurofascin, also impairs myelin sheath growth, likely reflecting its association in an adhesion complex at the axon-glial interface with Neurofascin. Caspr does not, however, affect myelin targeting, further indicating that Neurofascin independently regulates distinct aspects of CNS myelination by individual oligodendrocytes in vivo.

Ca 2+ activity signatures of myelin sheath formation and growth in vivo.

During myelination, individual oligodendrocytes initially over-produce short myelin sheaths, which are either retracted or stabilized. 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 stabilization, myelin sheaths grow along axons, and we find that higher-frequency Ca2+ transient activity in sheaths precedes faster elongation. Our data implicate local Ca2+ signaling in regulating distinct stages of myelination.

Individual Neuronal Subtypes Exhibit Diversity in CNS Myelination Mediated by Synaptic Vesicle Release.

Regulation of myelination by oligodendrocytes in the CNS has important consequences for higher-order nervous system function (e.g., [1-4]), and there is growing consensus that neuronal activity regulates CNS myelination (e.g., [5-9]) through local axon-oligodendrocyte synaptic-vesicle-release-mediated signaling [10-12]. 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.