Oligodendrocyte excitotoxicity determined by local glutamate accumulation and mitochondrial function.
Developing oligodendrocytes (OL precursors, pre-OLs) express alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype glutamate receptors (AMPARs) and are highly vulnerable to hypoxic-ischemic or oxygen-glucose deprivation (OGD)-induced excitotoxic injury, yet the mechanisms of injury remain unclear. Here we investigated the role of glutamate accumulation and mitochondrial function in OGD-induced pre-OL toxicity in vitro. Bulk glutamate concentration in the culture medium did not increase during OGD and OGD-conditioned medium did not transfer toxicity to naïve cells. Facilitation of glutamate diffusion by constant agitation of the culture reduced, while inhibition of glutamate diffusion by increasing medium viscosity with dextran enhanced, OGD-induced pre-OL injury. Depletion of extracellular glutamate by the glutamate scavenging system, glutamate-pyruvate transaminase plus pyruvate, attenuated pre-OL injury during OGD. Together these data suggest that local glutamate accumulation is critical for OGD toxicity. Interestingly, under normoxic conditions, addition of glutamate to pre-OLs did not cause receptor-mediated toxicity, but the toxicity could be unmasked by mitochondrial impairment with mitochondrial toxins. Furthermore, OGD caused mitochondrial potential collapse that was independent of AMPAR activation, and OGD toxicity was enhanced by mitochondrial toxins. These data demonstrate that pre-OL excitotoxicity is exacerbated by mitochondrial dysfunction during OGD. Overall, our results indicate that OGD-induced pre-OL injury is a novel form of excitotoxicity caused by the combination of local glutamate accumulation that occurs without an increase in bulk glutamate concentration and mitochondrial dysfunction. Therapeutic strategies targeting local glutamate concentration and mitochondrial injury during hypoxia-ischemia may be relevant to human disorders associated with pre-OL excitotoxicity.
Deng
Wenbin
W
Department of Neurology and Program in Neuroscience, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Yue
Qin
Q
Rosenberg
Paul A
PA
Volpe
Joseph J
JJ
Jensen
Frances E
FE
D000818:Animals; D000831:Animals, Newborn; D001562:Benzimidazoles; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002232:Carbocyanines; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D007476:Ionophores / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism / Q000648:ultrastructure*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D001562:Benzimidazoles; D002232:Carbocyanines; D018691:Excitatory Amino Acid Antagonists; D007476:Ionophores; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D018698:Glutamic Acid; D005947:Glucose; D002118:Calcium