Plasticity of Myelinating Glia

Abstract

Until recently, myelin has been considered a passive structural component of neural circuits, necessary for fast action potential propagation but not contributing in a dynamic way to nervous function. The possibility that myelin or myelinating cells might contribute to neural plasticity, other than in myelin repair, was not seriously considered. Indeed, the idea was strongly resisted or rejected outright by many experts. This conceptual barrier is now being dismantled by recent research that reveals plasticity of myelinating glia in a number of different contexts. This Special Issue explores this new and growing area of neuroscience through a collection of invited articles from some of the leaders in the field. Naturally, the selection of authors is far from comprehensive because of the constraint of physical space and our own limitations of imagination and persuasion as guest editors. Oligodendrocytes were the last major type of glial cell to be recognized, and their anatomy and function were initially mysterious. In contrast to astrocytes and microglia, some primary functions of which could be deduced by histology – showing, for example, astrocytes bridging between blood vessels and neurons, or microglia surrounding sites of injury – Schwann cell and oligodendrocyte functions were enigmatic. The slender cellular extensions from the oligodendrocyte cell body to axons could not be resolved by histological stains and microscopy in the era when Ramon y Cajal was feverously identifying cells in the brain and deducing their functions, so there was nothing to associate oligodendrocytes to axons anatomically or physiologically. Although Schwann cells were clearly evident as cells strung sequentially along axons in the peripheral nervous system, their function could not be deduced from their anatomy alone. Nothing suggested that Schwann cells and oligodendrocytes might be analogous to one another in any way. The main impediment to understanding both of these cell types was that neither the structure nor the function of myelin was understood. Even into the mid-twentieth century, myelin was regarded as a fatty substance that was extruded from axons. This substance coated some but not all axons (and none in invertebrate animals), leading Cajal to reject the proposal that myelin provided a vital function as electrical insulation, required for transmission of electrical impulses. Moreover, Schwann cells were considered by early anatomists to be vestigial cells that had formed the nerve axon during development by splicing together axonal segments into a continuous tube. Del Rio Hortega, an associate of Cajal s, perfected a method that stained the slender processes from oligodendrocytes, providing the critical missing evidence linking these cells to axons, an observation that was first confirmed by famed neurosurgeon Wilder Penfield in 1924. Ichiji Tasaki, through elegant single fibre electrophysiological studies, determined that action potentials were transmitted along myelinated fibres in a saltatory fashion, jumping rapidly from node to node. Electron microscopy in the 1950 s revealed the completely unexpected finding that the presumed fatty exudate from axons, myelin, was formed by a highly compacted series of membrane wrappings around the axon by Schwann cells in the PNS and oligodendrocytes in the CNS, an intricate intercellular junction seen in no other cellular context. Advances in imaging technology have been crucial for understanding the structure and plasticity of myelin and myelinating glia. This continues today both from advances in in vivo cellular imaging in live animals and from MRI brain imaging methods, such as diffusion tensor imaging, that resolve white matter microstructure and plasticity in the human brain. In this Special Issue, Hill and Grutzendler survey advances in live in vivo cellular imaging, including new fluorescence and label-free microscopic imaging methods, and describe how these new technologies are being used to illuminate the morphological plasticity of oligodendrocytes during myelin formation, remodeling, damage, and repair. Bells et al. review novel MRI brain imaging approaches that provide more specific information about white matter microstructure and plasticity in the human brain, in relation to cognitive development from childhood through adulthood. The intriguing idea that myelin plasticity improves information processing by optimizing synchrony of spike time arrival is addressed experimentally in their paper by assessing neural phase synchrony in visual cortex during a visual task in patients with recurrent demyelinating syndromes, compared to age-matched controls. This has revealed a correlation between white matter microstructure and neural synchronization in cognitive processing. Experimental evidence is accumulating from work with mice and zebrafish that electrical activity in axons can modulate myelin production and morphology at several levels, including the control of oligodendrocyte development and long-term survival, the rate of synthesis and assembly of myelin structural proteins, the length, number and thickness of myelin internodes elaborated by individual oligodendrocytes, and the micro-architecture of nodes of Ranvier and the paranodal regions. These features of myelin have the potential to influence impulse conduction speed as well as other “non-canonical” functions of oligodendrocytes such as metabolic coupling between oligodendrocytes and their associated axons, or increasing the maximum firing rate of the neuron-oligodendrocyte unit. Two articles in this issue by Foster, Bujalka and Emery and by Daumante, Lyons and Livesey deal with some of these concepts and mechanisms – collectively referred to as “adaptive myelination” – and the potential DOI: 10.1002/glia.23720