Treadmilling Model for Plasticity of the Myelin Sheath

Abstract

We propose a mechanism for myelin plasticity that would complement synaptic plasticity by adjusting conduction velocity for optimal spike-time arrival. In the proposed treadmilling model, myelin sheath thickness is a dynamic balance between the rates of new myelin deposited adjacent to the axon and removal of the outermost layer.

Keywords: astrocyte; myelin plasticity; neurofascin155; oligodendrocyte; spike-time dependent plasticity; thrombin.

Figure 2.

According to this model, the thickness of the myelin sheath is determined by two opposing processes, one (A) that adds additional wraps of myelin to the axon, and the other (B) that removes the outer layer. New layers of myelin are added beneath the overlaying layers by expansion of the inner tongue. Myelin is attached to the axon at the paranodal region flanking the node of Ranvier via septate-junctions, comprised of neurofascin 155 on myelin interacting with Contactin1-Caspr1 complex on the axon. Cleavage of neurofascin 155 by thrombin (red) can break this interaction, resulting in detachment of the outer paranodal loop from the axon, and withdrawal of the outer layer of myelin through the outer tongue. This increases nodal gap length and reduces myelin sheath thickness; both effects slow conduction velocity. Perinodal astrocytes at the nodes of Ranvier regulate this process by secreting thrombin inhibitors (green triangle), such as Protease Nexin1. The treadmilling process helps achieve optimal conduction velocity in individual axons. Whether action potentials influence the treadmilling process is not yet known, but if that turns out to be the case, myelin plasticity could complement synaptic plasticity in producing experience-dependent changes in neural circuits and learning.

Figure 1.. Myelin Formation and Structure.

Myelin is the electrically inert membrane wrapping on large diameter vertebrate axons that enables high-speed transmission of action potentials. In the CNS, the myelin sheath is formed by oligodendrocytes, which wrap multiple layers of compacted cell membrane around the axon (inset), forcing action potentials generated at nodes of Ranvier to relay rapidly from node to node. Astrocytes contact the nodes and interact with the paranodal region. Cytoplasm is extruded from the oligodendrocyte wrapping and the apposing membranes are fused by homophilic binding of myelin basic protein, forcing cytoplasm into a narrow channel at the perimeter of the sheath (cytoplasmic channel). The inner tongue expands around the axon to deposit multiple layers of compacted membrane around the axon, whereas the lateral edges attach to the axon through cell adhesion molecules, forming a spiral bordering the node of Ranvier, with the appearance of paranodal loops when sectioned. The outer tongue is continuous with the cell body of the oligodendrocyte through a slender process. Figure modified from [6].