Central axons preparing to myelinate are highly sensitivity to ischemic injury
Article first published online: 31 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 6, pages 936–951, December 2012
How to Cite
Alix, J. J. P., Zammit, C., Riddle, A., Meshul, C. K., Back, S. A., Valentino, M. and Fern, R. (2012), Central axons preparing to myelinate are highly sensitivity to ischemic injury. Ann Neurol., 72: 936–951. doi: 10.1002/ana.23690
- Issue published online: 31 DEC 2012
- Article first published online: 31 DEC 2012
- Accepted manuscript online: 16 JUL 2012 05:11PM EST
- Manuscript Accepted: 15 JUN 2012
- Manuscript Revised: 22 MAY 2012
- Manuscript Received: 10 FEB 2012
Vol. 75, Issue 3, 465, Article first published online: 1 APR 2014
Developing central white matter is subject to ischemic-type injury during the period that precedes myelination. At this stage in maturation, central axons initiate a program of radial expansion and ion channel redistribution. Here we test the hypothesis that during radial expansion axons display heightened ischemic sensitivity, when clusters of Ca2+ channels decorate future node of Ranvier sites.
Functionality and morphology of central axons and glia were examined during and after a period of modeled ischemia. Pathological changes in axons undergoing radial expansion were probed using electrophysiological, quantitative ultrastructural, and morphometric analysis in neonatal rodent optic nerve and periventricular white matter axons studied under modeled ischemia in vitro or after hypoxia–ischemia in vivo.
Acute ischemic 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 premyelinated axons proved 100% protective against acute ischemia studied under modeled ischemia in vitro or after hypoxia–ischemia in vivo.
Recent clinical data highlight the importance of axon pathology in developing white matter injury. The elevated susceptibility of early maturing axons to ischemic injury described here may significantly contribute to selective white matter pathology and places these axons alongside preoligodendrocytes as a potential primary target of both injury and therapeutics. ANN NEUROL 2012;72:936–951