Remodeling myelination: implications for mechanisms of neural plasticity

Abstract

One of the most significant paradigm shifts in membrane remodeling is the emerging view that membrane transformation is not exclusively controlled by cytoskeletal rearrangement, but also by biophysical constraints, adhesive forces, membrane curvature and compaction. One of the most exquisite examples of membrane remodeling is myelination. The advent of myelin was instrumental in advancing the nervous system during vertebrate evolution. With more rapid and efficient communication between neurons, faster and more complex computations could be performed in a given time and space. Our knowledge of how myelin-forming oligodendrocytes select and wrap axons has been limited by insufficient spatial and temporal resolution. By virtue of recent technological advances, progress has clarified longstanding controversies in the field. Here we review insights into myelination, from target selection to axon wrapping and membrane compaction, and discuss how understanding these processes has unexpectedly opened new avenues of insight into myelination-centered mechanisms of neural plasticity.

Figure 1

Structure of myelin and molecular domains along myelinated axons. (a) A neuron and the myelin sheaths along its axon. Myelin sheaths are made by oligodendrocytes in the CNS and by Schwann cells in the PNS. A single oligodendrocyte can generate multiple myelin sheaths, whereas an individual Schwann cell only makes one. The magnified view (bottom) shows the ultrastructure around the node of Ranvier. Glial membranes at the ends of the sheaths are attached to the axonal membrane flanking the node, forming paranodes. Paranodal loops contain cytoplasm and are not compacted. Neuron-glia interactions at paranodes form paranodal axoglial junctions with the characteristic electron-dense transverse bands under EM. M indicates the major dense line, I the intraperiod line. (b) An electron micrograph from a cross section of an adult mouse optic nerve, and its illustration. The major dense lines are clearly visualized, but the intraperiod lines are not obvious under this magnification. The ends of the myelin spiral are the outer and inner tongues, which contain cytoplasm and are not compacted. (c) Immunostaining of a postnatal day 22 mouse optic nerve shows three molecular domains around nodes of Ranvier. Blue, nodes positive for βIV spectrin; green, paranodal junctions positive for Caspr; red, juxtaparanodes positive for potassium channel Kv1.2. Most of the myelinated region is between two juxtaparanodes and not visualized here. Scale bars: 200 nm (b); 3 μm (c). Panel a adapted from ref. , Elsevier; micrograph in b courtesy of K. Susuki. For clarity, the g-ratio in b is not drawn to scale.

Figure 2

The current model of myelination in the CNS. An illustration of a virtually unrolled myelin sheet at each stage is shown at the top process of the oligodendrocyte. The corresponding cross-sections are displayed below the axon. From left to right: a newly differentiated oligodendrocyte extends a process to an unmyelinated axon. After contacting the axon, it starts wrapping by spreading its membrane. The growth zone for active membrane incorporation is shown in green. The myelin membrane grows both radially (more wraps) and longitudinally (longer sheath). When there are about three layers of myelin membrane, intracellular compaction initiates from the outermost layer toward the inner layers, preserving uncompacted cytoplasmic channels for material transport between the oligodendrocyte process and the growth zone. If a mature myelin sheath were unrolled from the axon, it would consist of a trapezoid of compacted membrane lined with a continuous cytoplasmic collar. When coiled around the axon, the lateral cytoplasmic collars form loops located at the paranodes (see Fig. 1a). Myelin retraction may occur during active myelination (represented by one missing process in the right-most oligodendrocyte). Adapted from ref. , Elsevier.

Figure 3

Intracellular compaction of myelin membranes. The illustration shows an actively forming myelin sheath with six lamellae. Compaction is completed for the two outermost layers and has not started for the two innermost layers. Compaction progresses both radially and longitudinally in parallel with membrane growth (see Fig. 2). In the longitudinal view, compaction of the two middle layers is still proceeding toward the paranodal loops. The inset shows a cross section of an area covering the outer tongue, compacted and uncompacted layers, and the inner tongue. In the region dominated by uncompacted myelin components, including CNP, the concentration of MBP is relatively low and the membranes are separated by the cytoplasm. After reaching a certain concentration, MBP closely binds two apposed membranes together and uncompacted myelin components and the cytoplasm are extruded; membranes are thereby compacted in a zipper-like fashion. Inset adapted from ref. , The Company of Biologists.