Dynamics of mature myelin

Abstract

Myelin, which is produced by oligodendrocytes, insulates axons to facilitate rapid and efficient action potential propagation in the central nervous system. Traditionally viewed as a stable structure, myelin is now known to undergo dynamic modulation throughout life. This Review examines these dynamics, focusing on two key aspects: (1) the turnover of myelin, involving not only the renewal of constituents but the continuous wholesale replacement of myelin membranes; and (2) the structural remodeling of pre-existing, mature myelin, a newly discovered form of neural plasticity that can be stimulated by external factors, including neuronal activity, behavioral experience and injury. We explore the mechanisms regulating these dynamics and speculate that myelin remodeling could be driven by an asymmetry in myelin turnover or reactivation of pathways involved in myelin formation. Finally, we outline how myelin remodeling could have profound impacts on neural function, serving as an integral component of behavioral adaptation.

Fig. 1 |. Myelin components and turnover.

a, Schematic of myelin, a highly organized structure with well-defined compartments. b, Myelin membranes have aunique constitution of lipidsthatare turned over at different rates. c, Myelin proteins localized to compact membranes (right) are turned over more slowly than proteins in non-compact myelin or at the myelin-axon junction (left; e.g. CNP and MAG, respectively). d, Lipids and proteins are added to mature myelin at the inner tongue and paranodal loops from trafficked vesicles and local translation. e, Membranes are removed from mature myelin via myelinoid bodies and concerted autophagy and endocytosis. Microglia and astrocytes, which phagocytose myelin in other contexts, could be involved in turnover of mature myelin. How the residual myelin sheath remains structurally organized and intact after multiple layers of myelin are removed is not fully understood.

Fig. 2 |. Myelin remodeling.

Numerous structural parameters of mature oligodendrocytes and myelin undergo remodeling over time or in response to neuronal activity, behavioral experience, injury, or genetic manipulation. The dynamics of each parameter are shown in isolation for clarity; however, remodeling of one parameter may impact another (e.g., internode and node length) and an individual sheath may undergo multiple structural changes.

Fig. 3 |. Potential functions of myelin remodeling.

a-d, Potential functional implications of myelin remodeling. a, Anaxon experiences internode formation, myelin thickening, and internode extension, causing accelerated or successful action potential conduction. b, An axon experiences internode removal, myelin thinning, and internode retraction, causing slowed or failed action potential conduction. Changes in conduction in a and b alter the synchrony of action potential arrival times. c, An axon experiences internode removal and retraction, enabling axonal remodeling. d, An axon experiences myelin thinning. Myelin lipidsare used for energy to support neuronal firing. e, Myelin remodeling occurs on axons involved in a specific behavior to modulate neuronal population activity.