Review articleMyelin plasticity in adulthood and aging
Introduction
A principal regulator of axonal conduction in the central nervous system is myelination, a multi-layered extension of compacted cell membrane formed by glial cells called oligodendrocytes. The tight wrapping of oligodendrocyte cell membrane around neuronal axons forms a structure that decreases axonal membrane capacitance and allows for saltatory conduction of action potentials. Myelin sheath generation, stability, length and thickness are all tightly regulated through molecular and biophysical cues arising from the axon and the local microenvironment [[1], [2], [3]]. Changes to any of these elements has the potential to modulate conduction velocity, an often overlooked but critical feature that can be used to precisely modify the timing and synchrony of signal arrival at distinct postsynaptic targets [[4], [5], [6]]. Differential conduction velocity accounts for a range of emergent neural circuit functions including, coincidence detection for sound localization in the auditory brainstem [7,8], electric organ discharge in electric fish [9], olivocerebellar processing in the cerebellum [10], thalamocortical processing in the somatosensory cortex [11], and timing of retinal ganglion cell inputs to the brain [12]. These examples likely reflect a widespread feature exploited by neural circuits to accomplish particular tasks by tuning conduction velocity to match circuit demands. Importantly, even with these examples, evidence for functional plasticity at the level of conduction velocity and how these types of signals are disrupted in disease is largely lacking. Understanding how fixed or flexible these structures are is critical to fully appreciate the mechanisms of neural network plasticity.
Oligodendrocytes are generated from a population of resident progenitor cells called NG2 glia (also commonly referred to as oligodendrocyte progenitor cells or OPCs) [[13], [14], [15]]. NG2 glia are resident in the adult brain and maintain the capacity to differentiate into mature myelinating oligodendrocytes. Oligodendrocyte differentiation is tightly regulated in different brain regions and at different developmental stages via a number of mechanisms, including differences in local axonal subtypes, neuronal activity, and phenotypic differences between local NG2 glia populations [2,16,17]. It is likely that these factors directly contribute to differences in the plasticity of myelin between gray and white matter regions.
Here we discuss and define the different types of plasticity exhibited by myelinating oligodendrocytes (summarized in Fig. 1). We outline what is currently known and yet to be discovered about these different forms of plasticity and we discuss how defects in myelination and mechanisms of plasticity could be involved in age-related cognitive decline.
Section snippets
Oligodendrocyte generation
The predominant form of myelin plasticity stems from the ability of oligodendrocytes to continuously be generated via terminal differentiation of NG2 glia (Fig. 1). Because of this, oligodendrocyte production and subsequent formation of new myelin internodes is not limited to a specific developmental window, potentially allowing for the myelination of previously unmyelinated or partially myelinated axons. Pulse chase fate-mapping experiments using thymidine analogue labeling of dividing cells
Myelin distribution
Different locations of the CNS display differing degrees of myelination, depending on the timing and extent of oligodendrocyte generation. Axons in some white matter regions, such as the optic nerve, are rapidly and almost completely myelinated early in development while axons in other regions, like the cerebral cortex, display a greater degree of coverage heterogeneity with myelination proceeding into adulthood [29,49,50]. Fully myelinated axons can be in close proximity to other partially or
Myelin thickness
Myelin’s ability to reduce the membrane capacitance of an axon is directly related to its thickness. Increased thickness bolsters the ability of the internode to insulate the covered axon and facilitate conduction. Axon caliber has long been thought to directly dictate sheath thickness in order to optimize functionality across morphologically distinct axons [60]. However, evidence has suggested that thickness may not be static and thus is not wholly dictated by axon diameter. Many of the
Myelin compaction
In addition to thickness, membrane compaction between individual layers and extrusion of the oligodendrocyte cytoplasm are also critically important for the function of myelin. Direct evidence for this comes from myelin basic protein deficient mice which have a defect in establishing compact myelin and develop a severe shivering phenotype [62]. In the peripheral nervous system, the myelin sheath maintains distinct cytoplasmic channels called Schmidt-Lanterman Incisures within an otherwise
Myelin internode length
New myelin sheath formation occurs during a defined period, lasting several hours, during which time pre-myelinating oligodendrocytes sample surrounding axons and begin sheath extension [41,43,68,69]. A proportion of oligodendrocyte cell processes which initiate extension subsequently mature into a stable myelin sheath while the rest retract shortly after formation and are lost. This suggests the existence of multiple checkpoints regulating myelin production from initial axon selection through
Node of Ranvier length
While myelin length, thickness, and compaction all play roles in facilitating axon conduction, structural changes at nodes of Ranvier may also play a role in tuning action potential velocity. A key characteristic of myelinated axons is the localization of voltage gated sodium channels to nodes of Ranvier [76]. In contrast, the same sodium channels are evenly distributed throughout the plasma membrane of unmyelinated axons. As the channels are confined to the nodes in myelinated axons, the
Myelin plasticity in aging
Evidence for myelin defects can be found in disorders that present during development and adolescence such as schizophrenia, bipolar disorder, and autism [82,83] in addition to diseases associated with adulthood and aging such as Alzheimer’s disease [84,85] and amyotrophic lateral sclerosis [86,87]. However, even in normal aging there is significant evidence that myelin defects are an early pathological hallmark that occurs in oligodendrocytes before other cells in the brain exhibit signs of
Conclusions
Myelin plasticity encompasses a range of potential changes in myelin structure, density, and function. These include the generation of new oligodendrocytes from their endogenous progenitors NG2 glia, to changes in myelin length, distribution, thickness, and compaction (summarized in Fig. 1). Each feature has the potential to modulate neural network function via alteration in synchronous arrival of signals at postsynaptic targets. The in vivo temporal dynamics and the distinct signals that
Acknowledgements
This work was supported by the following grants from the National Institutes of Health (USA): R00‐NS099469 and P20‐GM113132 and by a New Vision Award #CCAD201701 from the Donors Cure Foundation (USA) and a Fay/Frank Seed Grant #BRFSG-2019-01 from the Brain Research Foundation (USA) to R.A.H.
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