Mechanism of acute ischemic injury of oligodendroglia in early myelinating white matter: the importance of astrocyte injury and glutamate release.
In developing CNS white matter (WM), the period of early myelination is characterized by a heightened sensitivity to ischemic injury. Using an in situ (isolated) preparation, we show that the mechanism of acute ischemic injury of immature WM oligodendroglial involves Ca2+ influx though non-NMDA type glutamate receptors (GluRs). The Ca2+-influx and acute cell death that was evoked by ischemic conditions (oxygen and glucose withdrawal) in identified P10 rat optic nerve oligodendroglia were blocked by removing extracellular Ca2+ or by CNQX, a selective non-NMDA GluR antagonist. The selective Na-K-Cl cotransport (NKCC) inhibitor bumetanide was also highly protective, even though NKCC expression is restricted to astrocytes in this tissue. Bumetanide largely prevented the non-NMDA GluR-mediated [Ca2+]i rise evoked by ischemia in oligodendroglia, suggesting that it interfered with ischemic glutamate release. In control WM, glutamate-like reactivity was located mainly in astrocytes and oligodendroglia identified using ultrastructural criteria. In ischemic WM, astrocyte glutamate-like reactivity was reduced, an effect countered by bumetanide. We suggest a model in which NKCC-dependent injury and release of glutamate from astrocytes activates glutamate receptors on oligodendroglia, resulting in Ca2+-influx and acute cell death.
Department of Neurology, University of Washington, Seattle, Washington, USA.
Scott
S
Wilke
Robert
R
Thomas
Natalie
N
Allcock
Robert
R
Fern
D000208:Acute Disease; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D020318:Rats, Long-Evans
D018698:Glutamic Acid