Myelinated axon physiology and regulation of neural circuit function

The study of structural and functional plasticity in the central nervous system (CNS) to date has focused primarily on that of neurons and synapses. However, more recent studies implicate glial cells as key regulators of neural circuit function. Among these, the myelinating glia of the CNS, oligodendrocytes, have been shown to be responsive to extrinsic signals including neuronal activity, and in turn, tune neurophysiological function. Due to the fact that myelin fundamentally alters the conduction properties of axons, much attention has focused on how dynamic regulation of myelination might represent a form of functional plasticity. Here, we highlight recent research that indicates that it is not only myelin, but essentially all the function-regulating components of the myelinated axon that are responsive to neuronal activity. For example, the axon initial segment, nodes of Ranvier, heminodes, axonal termini, and the morphology of the axon itself all exhibit the potential to respond to neuronal activity, and in so doing might underpin specific functional outputs. We also highlight emerging evidence that the myelin sheath itself has a rich physiology capable of influencing axonal physiology. We suggest that to fully understand nervous system plasticity we need to consider the fact that myelinated axon is an integrated functional unit and adaptations that influence the entire functional unit are likely to underpin modifications to neural circuit function.