Oligodendrocytes assist in the maintenance of sodium channel clusters independent of the myelin sheath

Abstract

To ensure rapid and efficient impulse conduction, myelinated axons establish and maintain specific protein domains. For instance, sodium (Na+) channels accumulate in the node of Ranvier; potassium (K+) channels aggregate in the juxtaparanode and neurexin/caspr/paranodin clusters in the paranode. Our understanding of the mechanisms that control the initial clustering of these proteins is limited and less is known about domain maintenance. Correlative data indicate that myelin formation and/or mature myelin-forming cells mediate formation of all three domains. Here, we test whether myelin is required for maintaining Na+ channel domains in the nodal gap by employing two demyelinating murine models: (1) cuprizone ingestion, which induces complete demyelination through oligodendrocyte toxicity; and (2) ceramide galactosyltransferase deficient mice, which undergo spontaneous adult-onset demyelination without oligodendrocyte death. Our data indicate that the myelin sheath is essential for long-term maintenance of sodium channel domains; however, oligodendrocytes, independent of myelin, provide a partial protective influence on the maintenance of nodal Na+ channel clusters. Thus, we propose that multiple mechanisms regulate the maintenance of nodal protein organization. Finally, we present evidence that following the loss of Na+ channel clusters the chronological progression of expression and reclustering of Na+ channel isoforms during the course of CNS remyelination recapitulates development.

Early events in node of Ranvier formation during myelination and remyelination in the PNS

“…These data indicate that oligodendrocytes actively regulate the complement and localization of Nav channels expressed in CNS axons. Consistent with this idea, Dupree et al (2004) reported, using the cuprizone model of CNS demyelination and remyelination, that demyelinated CNS axons have clusters of Nav1.2 channels, and that nodes in the remyelinated corpus callosum eventually have only Nav1.6 channels. Thus, clustering of Nav channels during CNS remyelination might recapitulate developmental myelination.…”

“…The phenomenon of reversion from Nav1.6 as the main Nav channel subunit in axons to Nav1.2 as the main channel subunit is not restricted to mutant mouse models, but also occurs after demyelination in multiple sclerosis (Craner et al, 2004b). Interestingly, Dupree et al (2004) detected Nav1.2 clusters during remyelination in the CNS (in the corpus callosum), similar to those seen during developmental myelination.…”

“…4e,f). Thus, in contrast to the CNS (Dupree et al, 2004), new nodes of Ranvier that form during PNS remyelination contain Nav1.6.…”

“…Subsequent studies show that after demyelination in the CNS, Nav1.6 channel clusters are lost and there is a dramatic increase in Nav1.2 protein along the axon, which indicates that myelin actively regulates the localization and kinds of channels that occur in axons (Craner et al, 2003;Rasband et al, 2003a). Furthermore, during remyelination in the CNS Nav1.2 channels cluster at newly forming nodes of Ranvier (Dupree et al, 2004).…”

Absence of 2-Hydroxylated Sphingolipids Is Compatible with Normal Neural Development But Causes Late-Onset Axon and Myelin Sheath Degeneration

“…Deletion of oligodendrocyte-specific expressed genes can have a dramatic effect on axon maintenance and localization of neuronal proteins without strongly affecting myelin structure (Griffiths et al, 1998;Lappe-Siefke et al, 2003;GarciaFresco et al, 2006). Oligodendrocytes also are important for nodal sodium channel clustering, and this seems to be independent of myelin (Dupree et al, 2005). Combined deletion of FGF receptor-2 and CNP in oligodendrocytes led to massive hyperactivity, possibly as a result of an indirect effect of oligo- Ϫ/Ϫ (B) mice, which were morphologically indistinguishable.…”