Myelinated axon physiology and regulation of neural circuit function

Abstract

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.

Genetic Variation in CNS Myelination and Functional Brain Connectivity in Recombinant Inbred Mice

“…Accordingly, we found that myelinated fibers of DBA had smaller axon diameters and thinner myelin. The diameter of myelinated axons is a well-known feature that influences the speed of signal transduction in axons [54]. Interestingly, smaller caliber myelinated fibers are reported for mutant mice for each of the myelin proteins that we observed which are lower expressed in DBA mice: MAG, MOBP and CNP [52,[60][61][62], which is in line with the established concept that proper myelination provides, as well as insulation, also trophic support for axons, thereby increasing axon caliber [2].…”

“…To further investigate myelin protein differences between C57 and DBA at 2 months of age, EM analysis was performed on optic nerves, a CNS structure in which all axons are myelinated, making it possible to determine small differences in CNS myelination ( Figure 5) [1,2,50,[52][53][54]. No differences in g-ratio were found between C57 and DBA, whereas the myelin thickness was smaller in DBA compared with C57 ( Figure 5).…”

Neuronal activity disrupts myelinated axon integrity in the absence of NKCC1b

“…For example, it has been proposed that electrical conduction through the periaxonal space between the axon and the overlying myelin sheath also contributes to the fundamental nature of conduction along myelinated axons ( Cohen et al, 2020 ). Indeed, numerous ion channels, transporters, and neurotransmitter receptors are present at the axon–myelin interface and are thus well placed to regulate myelinated axon physiology, structure, and integrity ( Suminaite et al, 2019 ). These include axonal ion channels, including potassium (K + ) channels, that extrude ions into the periaxonal space upon neuronal activity and channels in the juxtaposed myelin sheath that buffer ions, including K + , from the periaxonal space ( Rash et al, 2016 ; Wang et al, 1993 ; Schirmer et al, 2018 ; Larson et al, 2018 ).…”

Myelination Increases the Spatial Extent of Analog-Digital Modulation of Synaptic Transmission: A Modeling Study

“…During development, the number of myelin lamellae increases from 0 before birth to maximal levels before sexual maturity (Berthold and Carlstedt, 1982). The myelin thickness also depends on electrical activity (Kaller et al, 2017;Suminaite et al, 2019). Therefore, our model suggests that ADFs spatial extent may increase during the development and vary as a function of neuronal electrical activity.…”