Calcium-permeable AMPA/kainate receptors mediate toxicity and preconditioning by oxygen-glucose deprivation in oligodendrocyte precursors.
Hypoxic-ischemic brain injury in premature infants results in cerebral white matter lesions with prominent oligodendroglial injury and loss, a disorder termed periventricular leukomalacia (PVL). We have previously shown that glutamate receptors mediate hypoxic-ischemic injury to oligodendroglial precursor cells (OPCs) in a model of PVL in the developing rodent brain. We used primary OPC cultures to examine the mechanism of cellular toxicity induced by oxygen-glucose deprivation (OGD) to simulate brain ischemia. OPCs were more sensitive to OGD-induced toxicity than mature oligodendrocytes, and OPC toxicity was attenuated by nonselective [2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX), 6-cyano-7-nitroquinoxaline-2,3-dione], alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring (GYKI 52466), kainate-preferring (gamma-d-glutamylaminomethanesulfonic acid), or Ca2+-permeable AMPA/kainate receptor antagonists (joro spider toxin, JSTx) administered either during or after OGD. Furthermore, NBQX or JSTx blocked OGD-induced Ca2+ influx. Relevant to recurrent hypoxic-ischemic insults in developing white matter, we examined the effects of sublethal OGD preconditioning. A prior exposure of OPCs to sublethal OGD resulted in enhanced vulnerability to subsequent excitotoxic or OGD-induced injury associated with an increased Ca2+ influx. AMPA/kainate receptor blockade with NBQX or JSTx either during or after sublethal OGD prevented its priming effect. Furthermore, OGD preconditioning resulted in a down-regulation of the AMPA receptor subunit GluR2 on cell surface that increased Ca2+ permeability of the receptors. Overall, these data suggest that aberrantly enhanced activation of Ca2+-permeable AMPA/kainate receptors may be a major mechanism in acute and repeated hypoxic-ischemic injury to OPCs in disorders of developing cerebral white matter, such as PVL.
Deng
Wenbin
W
Department of Neurology and Program in Neuroscience, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Rosenberg
Paul A
PA
Volpe
Joseph J
JJ
Jensen
Frances E
FE
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology*; D018092:Kainic Acid Receptors / Q000502:physiology*
D002118:Calcium; D005947:Glucose; D010100:Oxygen; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors