Simultaneous Ablation of Neuronal Neurofascin and Ankyrin G in Young and Adult Mice Reveals Age-Dependent Increase in Nodal Stability in Myelinated Axons and Differential Effects on the Lifespan.

Nodes of Ranvier are unique regions where voltage-gated sodium channels are highly enriched to drive saltatory conduction. Genetic ablations in adult mice with loss of specific nodal proteins causes slow but progressive nodal deterioration associated with decreased nerve conduction and axonopathy. What has remained unaddressed is whether loss of nodal proteins at different time points in postnatal life follows similar timelines of nodal disorganization. Here we utilized simultaneous ablation of Neurofascin (NF186) and Ankyrin G (AnkG) in mice of both sexes at three specific time points. We report that concurrent ablation of these core nodal components at postnatal day 13 (P13) leads to accelerated nodal destabilization in comparison with P23, and this disorganization is even slower when ablated at P93. Ablation of NF186 with AnkG at P13 reduced the half-life of NF186 to 15 days compared to 1 month at P23, which increased to 2 months at P93, indicating increasing nodal stability. The half-life of AnkG at the nodes also increased with age but showed enhanced disappearance from the node in the absence of NF186, with a half-life of 3 days at P13 ablation. The nodal disorganization occurred in a sequential manner, with AnkG disappearing first from the nodal areas irrespective of the timing of ablation, and led to decreased nerve conduction and affected axonal health. Together, our studies reveal that nodes of Ranvier in myelinated axons continue to become more stable with age and suggest that nodal disorganization in adult human demyelinating disorders occurs slowly until neurological symptoms become evident.