Glutamate receptor-mediated ischemic injury of premyelinated central axons

Ann Neurol. 2009 Nov;66(5):682-93. doi: 10.1002/ana.21767.


Objective: Ischemic injury of axons is a feature of periventricular leukomalacia, a pathological correlate of cerebral palsy. Recent evidence suggests that axons are damaged before they receive the first layer of compact myelin. Here we examine the cellular mechanisms underlying ischemic-type injury of premyelinated central axons.

Methods: Two-thirds of axons in the postnatal day 10 (P10) rat optic nerve are small premyelinated axons (<0.4microm in diameter), and one-third have undergone radial expansion in preparation for glial contact and the onset of myelination. Compound action potential recording and quantitative electron microscopy were used to examine the effect of modeled ischemia (oxygen-glucose deprivation) upon these two axon populations. Glutamate receptor (GluR) expression was investigated using polymerase chain reaction (PCR) and immunostaining approaches at the confocal light and ultrastructural levels.

Results: Oxygen-glucose deprivation produced action potential failure and focal breakdown of the axolemma of small premyelinated axons at sites of contact with oligodendrocyte processes, which were also disrupted. The resulting axon loss was Ca(2+)-dependent, Na(+)- and Cl(-)-independent, and required activation of N-methyl-D-aspartic acid (NMDA) and non-NMDA GluRs. NMDA receptor expression was localized to oligodendrocyte processes at sites of contact with premyelinated axons, in addition to expression within compact myelin. No periaxonal NMDA receptor expression was observed on oligodendrocyte processes ensheathing large premyelinated axons and no protective effect of GluR block was observed in these axons.

Interpretation: NMDA receptor-mediated injury to oligodendrocyte processes navigating along small premyelinated axons precedes damage to the underlying axon, a phenomena that is lost following radial expansion and subsequent oligodendrocyte ensheathment.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / physiology
  • Acute Disease
  • Animals
  • Animals, Newborn
  • Axons / pathology*
  • Axons / ultrastructure
  • Ischemia / metabolism*
  • Ischemia / pathology*
  • Myelin Sheath / pathology*
  • Myelin Sheath / ultrastructure
  • Nerve Fibers, Myelinated / pathology*
  • Nerve Fibers, Myelinated / ultrastructure
  • Optic Nerve / blood supply*
  • Optic Nerve / physiology*
  • Rats
  • Receptors, Glutamate / physiology*


  • Receptors, Glutamate