A new mechanism of nervous system plasticity: activity-dependent myelination

Abstract

The synapse is the focus of experimental research and theory on the cellular mechanisms of nervous system plasticity and learning, but recent research is expanding the consideration of plasticity into new mechanisms beyond the synapse, notably including the possibility that conduction velocity could be modifiable through changes in myelin to optimize the timing of information transmission through neural circuits. This concept emerges from a confluence of brain imaging that reveals changes in white matter in the human brain during learning, together with cellular studies showing that the process of myelination can be influenced by action potential firing in axons. This Opinion article summarizes the new research on activity-dependent myelination, explores the possible implications of these studies and outlines the potential for new research.

Figure 1 |. Development of oligodendrocytes.

Oligodendrocyte progenitor cells (OPCs) differentiate into multipolar premyelinating oligodendrocytes, which mature into myelinating oligodendrocytes. OPCs constitute the majority of mitotic cells in the adult brain, and mature oligodendrocytes can form myelin segments on multiple axons simultaneously.

Figure 2 |. Myelin and the node of Ranvier.

a | Oligodendrocytes form myelin on axons to enable high-speed impulse transmission via saltatory conduction. b | Action potentials are generated at nodes of Ranvier situated periodically along the axon between internodal segments of axons insulated by compact myelin. Perinodal astrocytes are in contact with the axon at nodal regions. c | Transmission electron micrograph of mouse optic nerve axons in cross section, showing the multiple layers of compact myelin (My) and wrapping axons (Ax). d | Longitudinal section through an axon through the node of Ranvier, illustrating the axon perinodal astrocyte, nodal (N) paranodal (P) and internodal axon regions as shown in part b. e | Three-dimensional reconstruction of the node of Ranvier from serial blockface electron microscopy (compact myelin is shown in purple and perinodal astrocytes are shown in blue, with the axon being depicted in yellow).

Figure 3 |. Changes in white matter tracts after learning.

a | Apparatus used to train rats to grasp a food pellet prior to analysis of brain structure by MRI to detect possible cellular changes during learning. b | After training rats to grasp a food reward, brain imaging by MRI showed higher fractional anisotropy (FA) in white matter tracts in the somatomotor areas of the hemisphere contralateral to the trained paw (higher FA indicated in red). Higher FA represents more highly polarized water diffusion in tissue as a consequence of more highly organized cellular structure. FA is increased by myelination, which restricts water diffusion more linearly along axons. c | Learning rate correlated significantly with the extent of white matter structure (FA). d | The intensity of immunocytochemical staining for myelin basic protein (MBP; brown staining, indicated by white arrows) was significantly higher in animals that had received training (skilled reaching (SR)) than in animals undergoing an equivalent amount of grasping activity but without a learning task (unskilled reaching (UR)), consistent with increased myelination of axons after motor learning. e | The increase in MBP staining was in proportion to the rate of learning, suggesting that learning proficiency was directly correlated with the increase in the level of myelination after motor training. Parts b–e are adapted with permission from REF. , Society for Neuroscience.

Figure 4 |. Non-synaptic junctions on myelinating glia promote preferential myelination of electrically active axons.

a | Oligodendrocyte progenitor cells (OPCs) were co-cultured with a mixture of mouse dorsal root ganglion neurons in which vesicle release from axons was blocked by botulinum toxin (BnTX; red axons) or was not blocked (yellow axons). The experiments show that myelination by oligodendrocytes is preferentially induced on electrically active axons releasing vesicles. b | Specialized contacts form between axons and oligodendrocyte cell processes, which lack the morphological and electrophysiological features of synapses but signal via release of neurotransmitters (glutamate and ATP) from axons. Neurotransmitters released at non-synaptic axo-glial junctions signal electrical activity in axons to oligodendrocytes and cause an increase in intracellular Ca²⁺ in the glial cell. c | Electrical stimulation of axons causes release of glutamate from vesicles that activate NMDA receptor (NMDAR) and metabotropic glutamate receptor (mGluR) on oligodendrocyte cell processes. This in turn triggers formation of the axoglial signalling complex (involving the SRC family kinase FYN, cell adhesion molecules (CAMs) L1CAM) and F3 (also known as contactin), laminin and integrin) and phosphorylation of FYN. Activated FYN phosphorylates heterogeneous nuclear ribonucleoprotein A2, resulting in local myelin basic protein (MBP) translation from mRNA in oligodendrocyte cell processes. The graph in the right-hand panel demonstrates that formation of the axo-glial signalling complex and local synthesis of MBP are inhibited by axonal firing when NMDAR and mGluR activation are blocked by BnTX. d | Three weeks after stimulating action potentials in axons, the number and length of myelin segments formed on axons releasing synaptic vesicles (yellow axons in diagram on the left and blue bars in graphs on the right) was much higher than on axons in which vesicle release was not blocked by BnTX. AAAAAA, poly(A) tail of mRNA. Parts b–d are from REF. , Nature Publishing Group. Part c is also from Wake, H., Lee, P. R. & Fields, R. D. Control of local protein synthesis and initial events in myelination by action potentials. Science 333, 1647–1651 (2011). Reprinted with permission from AAAS.

Figure 5 |. Myelin stabilization is promoted by vesicle release from axons in zebrafish.

a | Studies in zebrafish show that 75% of initial myelination attempts on axons (‘nascent myelin sheaths’) fail within 90 minutes. b | More frequent retraction of newly formed myelin is observed on axons in which vesicle release is inhibited by tetanus toxin (TnTX; red). c | Decreased stabilization of myelin on axons with vesicle release inhibited by TnTX leads to fewer myelin sheaths being retained on axons expressing TnTX (red) compared with controls (blue). Data for this figure combine information from REFS ,. The graph in part c is from REF. , Nature Publishing Group.

Figure 6 |. Activity-dependent myelination in nervous system plasticity and learning.

Information processing, synaptic plasticity and learning are highly dependent on precise spike-time arrival at relay points in neural circuits, and thus the optimal conduction velocity in individual axons in a circuit is critical. a | Hypothetical circuit. Neurons shown in purple are the subject of parts b and c. b | Before learning, non-synchronous arrival of action potentials would inhibit processes that strengthen synaptic transmission in response to coincident firing of the pre- and postsynaptic membrane. c | After learning, activity-dependent effects on myelination could adjust conduction velocity to optimize synchronous arrival of action potential input from converging circuits.