Objective: Developing central white matter is subject to ischaemic-type injury during the period that precedes myelination. At this stage in maturation, central axons initiate a programme of radial expansion and ion channel re-distribution. Here we test the hypothesis that during radial expansion axons display heightened ischaemic sensitivity, when clusters of Ca2+ channels decorate future node of Ranvier sites.
Methods: Functionality and morphology of central axons and glia were examined during and after a period of modeled ischaemia. Pathological changes in axons undergoing radial expansion were probed using electrophysiological, quantitative ultrastructural and morphometric analysis in neonatal rodent optic nerve and peri-ventricular white matter axons studied under modeled ischaemia in vitro or after hypoxia-ischaemia in vivo.
Results: Acute ischaemic injury of central axons undergoing initial radial expansion was mediated by Ca2+ influx through Ca2+ channels expressed in axolemma clusters. This form of injury operated only in this axon population, which was more sensitive to injury than neighboring myelinated axons, smaller axons yet to initiate radial expansion, astrocytes or oligodendroglia. A pharmacological strategy designed to protect both small and large diameter pre-myelinated axons proved 100% protective against acute ischaemia studied under modeled ischaemia in vitro or after hypoxia-ischaemia in vivo.
Interpretation:Recent clinical data highlight the importance of axon pathology in developing white matter injury. The elevated susceptibility of early maturing axons to ischaemic injury described here may significantly contribute to selective white matter pathology and places these axons alongside pre-oligodendrocytes as a potential primary target of both injury and therapeutics.