Myelin plasticity in adulthood and aging

Highlights

• Myelin plasticity occurs throughout development and adulthood.

• Myelin plasticity ranges from the generation of new oligodendrocytes to fine structural changes in the myelin sheath.

• Various environmental cues can induce myelin plasticity.

• Defects in myelin maintenance are likely involved in age-related cognitive decline.

Abstract

The central nervous system maintains the potential for molecular and cellular plasticity throughout life. This flexibility underlies fundamental features of neural circuitry including the brain’s ability to sense, store, and properly adapt to everchanging external stimuli on time scales from seconds to years. Evidence for most forms of plasticity are centered around changes in neuronal structure and synaptic strength, however recent data suggests that myelinating oligodendrocytes exhibit certain forms of plasticity in the adult. This plasticity ranges from the generation of entirely new myelinating cells to more subtle changes in myelin sheath length, thickness, and distribution along axons. The extent to which these changes dynamically modify axonal function and neural circuitry and whether they are directly related to mechanisms of learning and memory remains an open question. Here we describe different forms of myelin plasticity, highlight some recent evidence for changes in myelination throughout life, and discuss how defects in these forms of plasticity could be associated with cognitive decline in 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.