Myelin Dynamics at the Axon–Oligodendrocyte Interface: Adaptive Conduction Homeostasis in Demyelination, Remyelination and White Matter Repair

In the past, myelination was perceived as a passive, multilayered structure that increased the velocity with which signals travel along an axon. However, evidence now indicates that this conceptualization does not reflect the dynamic processes occurring during the continuous maintenance of signal transmission. Therefore, our hypothesis in this paper is to view myelination as an interactive boundary between the oligodendrocytes enveloping an axon and the axon itself. These cells interact to coordinate several factors, including geometry, membrane structure, nanoscale barriers, cellular accessibility, and metabolic status. For example, TMEM63A mediates Ca2+ mechanotransduction in response to mechanical deformation of the sheath, Importin-13 organizes neurofilament localization, and MYO5A supports delivery of Mbp mRNA to sites of local protein synthesis. Additional molecular mechanisms include glycolipid transfer via GLTP for replenishing lipids within the sheath, choline uptake for facilitating sheath lipid renewal, mTOR-mediated regulation of lipid synthesis for supporting sheath composition, and SNAP-23-dependent membrane fusion for providing new membrane components to the sheath. Other mechanisms have been identified to support node and paranode formation necessary for electrical separation. The noncompact regions of the sheath provide additional routes for nonelectrical organelle and cargo movement through the outer-tongue–paranodal-loop–inner-tongue pathway. Lastly, the periaxonal space acts to coordinate ionic, metabolic, and oxidative exchange around the axon. Monocarboxylate transporters are linked to fatty-acid oxidation and lactate-based protein and histone modification such that metabolic flux can be utilized to maintain sheath integrity. We therefore define adaptive conduction homeostasis as the process required to coordinate all of these functions so that the fidelity, velocity, repetitive-firing reliability, and metabolic stability of action-potential propagation are maintained.