Hypoxia—Ischemia Preferentially Triggers Glutamate Depletion from Oligodendroglia and Axons in Perinatal Cerebral White Matter

Abstract

Ischemia is implicated in periventricular white matter injury (PWMI), a lesion associated with cerebral palsy. PWMI features selective damage to early cells of the oligodendrocyte lineage, a phenomenon associated with glutamate receptor activation. We have investigated the distribution of glutamate in rat periventricular white matter at post-natal day 7. Immuno-electron microcopy was used to identify O4( + ) oligodendroglia in control rats, and a similar approach was employed to stain glutamate in these cells before and after 90 mins of hypoxia-ischemia. This relatively brief period of hypoxia-ischemia produced mild cell injury, corresponding to the early stages of PWMI. Glutamatelike reactivity was higher in oligodendrocytes than in other cell types (2.1360.25 counts/lm 2 ), and declined significantly during hypoxia-ischemia (0.9360.15 counts/lm 2 : P < 0.001). Astrocytes had lower glutamate levels (0.760.07 counts/lm 2 ), and showed a relatively small decline during hypoxiaischemia. Axonal regions contained high levels of glutamate (1.8460.20 counts/lm 2 ), much of which was lost during hypoxia-ischemia (0.7260.20 counts/lm 2 : P > 0.001). These findings suggest that oligodendroglia and axons are the major source of extracellular glutamate in developing white matter during hypoxia-ischemia, and that astrocytes fail to accumulate the glutamate lost from these sources. We also examined glutamate levels in the choroid plexus. Control glutamate levels were high in both choroid epithelial (1.9060.20 counts/lm 2 ), and ependymal cells (2.2060.28 counts/ lm 2 ), and hypoxia-ischemia produced a large fall in ependymal glutamate (0.9760.08 counts/lm 2 : P > 0.001). The ependymal cells were damaged by the insult and represent a further potential source of glutamate during ischemia.

Functional glutamate transport in rodent optic nerve axons and glia

“…Thomas et al (2004) also demonstrated a high resting intracellular glutamate levels in oligodendrocytes that was elevated following ischemia, suggesting both effective glutamate uptake under normal conditions and the absence of uptake reversal during ischaemia. It is not known how [Na + ] i , pH i and membrane potential are affected by ischemia in these cells but it would appear that the conditions are not met for significant reversal of glutamate uptake in this preparation (but see Back et al 2006). The current findings suggest that glutamate release from axons via reverse transport is a potentially important factor in excitotoxic (Dewar et al, 2003;Wilke et al, 2004) and non-excitotoxic (Oka et al, 1993) white matter damage during ischemia.…”

Methylene Blue Reduces Acute Cerebral Ischemic Injury via the Induction of Mitophagy

“…The tissue samples were handled as reported previously (39). Briefly, brain section was quickly cut into 1 mm cubes, immersion-fixed with 2.5% glutaraldehyde in 0.1 mol/L phosphate buffer (pH 7.4) overnight at 4°C and fixed in 1% buffered osmium tetroxide.…”

White Matter Axon Vulnerability to AMPA/Kainate Receptor-Mediated Ischemic Injury Is Developmentally Regulated

“…In adult WM, ischemic injury is mediated by AMPA/kainate receptors (Tekkök and Goldberg, 2001). During ischemia, axons and OLs release glutamate, resulting in activation of WM glutamate receptors and cellular injury (Li et al, 1999;Back et al, 2007). Does glutamate injure axons directly?…”