Reassembly of Excitable Domains after CNS Axon Regeneration

Abstract

Action potential initiation and propagation in myelinated axons require ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Disruption of these domains after injury impairs nervous system function. Traditionally, injured CNS axons are considered refractory to regeneration, but some recent approaches challenge this view by showing robust long-distance regeneration. However, whether these approaches allow remyelination and promote the reestablishment of AIS and nodes of Ranvier is unknown. Using mouse optic nerve crush as a model for CNS traumatic injury, we performed a detailed analysis of AIS and node disruption after nerve crush. We found significant disruption of AIS and loss of nodes within days of the crush, and complete loss of nodes 1 week after injury. Genetic deletion of the tumor suppressor phosphatase and tensin homolog (Pten) in retinal ganglion cells (RGCs), coupled with stimulation of RGCs by inflammation and cAMP, dramatically enhanced regeneration. With this treatment, we found significant reestablishment of RGC AIS, remyelination, and even reassembly of nodes in regions proximal, within, and distal to the crush site. Remyelination began near the retina, progressed distally, and was confirmed by electron microscopy. Although axons grew rapidly, remyelination and nodal ion channel clustering was much slower. Finally, genetic deletion of ankyrinG from RGCs to block AIS reassembly did not affect axon regeneration, indicating that preservation of neuronal polarity is not required for axon regeneration. Together, our results demonstrate, for the first time, that regenerating CNS axons can be remyelinated and reassemble new AIS and nodes of Ranvier.

Structural adaption of axons during de‐ and remyelination in the Cuprizone mouse model

“…In this study, even the compound action potential could not be restored to normal levels, due to the damage of axons after complete demyelination, as shown by increase of ß‐APP . Despite these findings, nodes of Ranvier can be reestablished if remyelination is successful highlighting the capacity for regeneration of CNS. There seems to be a threshold at which level of demyelination, irreversible axonal loss, disruption of sodium channel clusters and reduction of sodium channels occur.…”

Myelin status and oligodendrocyte lineage cells over time after spinal cord injury: What do we know and what still needs to be unwrapped?

“…When ion channels are properly organized in this way, action potentials “jump” from node to node, thereby significantly increasing conduction velocity. This highly structured organization of axonal proteins depends on physical associations between axonal proteins and proteins expressed by myelin at the paranodal loops, revealing that myelin plays an active role in axon structure (Chang et al, ; Dupree, Girault, & Popko, ; Marin et al, ; C. Zhang & Rasband, ). When axons lose their myelin sheath, nodal proteins diffuse, intermingle and lose their highly organized distribution on the axon, thereby preventing saltatory conduction.…”

Can injured adult CNS axons regenerate by recapitulating development?

“…Neurotrophin 3 expression guides sensory axon regeneration and synapse formation but the axons remain unmyelinated (Alto et al, 2009). In contrast, after Pten knockout, cAMP administration and inflammatory stimulation, regenerating RGC axons are myelinated and assemble nodes of Ranvier (Marin et al, 2016). After NPCs are transplanted into the injured spinal cord and differentiate into neurons that extend axons long distances, about a quarter of their axons are myelinated by host oligodendrocytes (Hunt et al, 2017).…”