Functional and structural properties of ion channels at the nerve terminal depends on compact myelin

Abstract

Axon myelination increases the conduction velocity and precision of action potential propagation. Although the negative effects of demyelination are generally attributed to conduction failure, accumulating evidence suggests that myelination also regulates the structural properties and molecular composition of the axonal membrane. In the present study, we investigated how myelination affects ion channel expression and function, particularly at the last axon heminode before the nerve terminal, which regulates the presynaptic excitability of the nerve terminal. We compared the structure and physiology of normal axons and those of the Long-Evans shaker (LES) rat, which lacks compact myelin. The normal segregation of Na(+) channel expression and dynamics at the heminode and terminal was lost in the LES rat. Specifically, NaV -α subunits were dispersed and NaV β4 subunit was absent, whereas the density of K(+) channels was increased at the heminode. Correspondingly, resurgent and persistent Na(+) currents were reduced and K(+) current was increased. Taken together, these data suggest a specific role for compact myelin in the orchestration of ion channel expression and function at the axon heminode and in regulating excitability of the nerve terminal.

Resistance to action potential depression of a rat axon terminal in vivo

“…Surprisingly, Na v 1.6 intensity was highest in the terminal itself (Fig. S9B), in contrast to a previous report (33), which might be related to the early developmental stage, at which no heminode has yet been formed (34,35). We conclude that Na v 1.6 is already present at the calyx of Held shortly after its formation.…”

“…The combination of a steady-state depression with a time-dependent recovery adequately described the observed AP depression, suggesting that the fast recovery of calyceal sodium channels from inactivation (33) provided a reasonable description of the recovery from AP depression. Immunolabeling evidence was obtained for the early presence of Na v 1.6, which is known for its swift kinetics and resistance to inactivation during high-frequency firing (36); the presence of Na v 1.6 is in agreement with studies at the calyx of Held at later developmental stages (33,34,35). No evidence was found for the presence of heminodes, which do not form until the second postnatal week, presumably triggered by myelination (15,34,35,37).…”

“…Immunolabeling evidence was obtained for the early presence of Na v 1.6, which is known for its swift kinetics and resistance to inactivation during high-frequency firing (36); the presence of Na v 1.6 is in agreement with studies at the calyx of Held at later developmental stages (33,34,35). No evidence was found for the presence of heminodes, which do not form until the second postnatal week, presumably triggered by myelination (15,34,35,37). An increase in glial coverage and the replacement of the cup shape by the calyceal fingers precluded an investigation of the properties of the mature calyx in vivo.…”

Presynaptic mitochondria volume and abundance increase during development of a high-fidelity synapse

“…Na + channels are highly clustered 685 at the heminode and excluded from the terminal (Leao et al, 2005). Although the last heminode 686 in the mature calyx axon is well-defined using confocal imaging (Berret et al, 2016;Xu et al, 687 2017), we had difficulty defining the heminode from the myelination morphology only. Despite 688 this, we were unable to detect any local increases in mitochondrial densities along the last 5-50 µm 689 of the axons in the reconstructed volume.…”

Myelinated axon physiology and regulation of neural circuit function

“…Transient, persistent and resurgent Na v ‐mediated currents, originating from the axon heminode, are critical for the reliability and temporal fidelity of presynaptic spikes (Huang & Trussell, ; J. Hee Kim, Kushmerick, & von Gersdorff, ). Animal models with no compact myelin exhibit a reduced reliability of presynaptic firing and impaired temporal fidelity of synaptic transmission during high‐frequency firing, thought to be primarily because of dysregulation of Na v ‐channel localization at the terminal heminode (Berret, Kim, Lee, Kushmerick, & Kim, ; J. H. Kim, Renden, & von Gersdorff, ). Importantly, heminodal ion channel composition is activity‐dependent, indicating that heminodes might be accutely tuned to mediate specific conduction properties (Grubb & Burrone, ; Xu, Berret, & Kim, ).…”