Hypoxia/ischemia depletes the rat perinatal subventricular zone of oligodendrocyte progenitors and neural stem cells.
Cerebral hypoxia/ischemia of the newborn has a frequency of 4/1,000 births and remains a major cause of cerebral palsy, epilepsy, and mental retardation. Despite progress in understanding the pathogenesis of hypoxic-ischemic injury, the data are incomplete regarding the mechanisms leading to permanent brain injury. Here we tested the hypothesis that cerebral hypoxia/ischemia damages stem/progenitor cells in the subventricular zone (SVZ), resulting in a permanent depletion of oligodendrocytes. We used a widely accepted rat model and examined animals at recovery intervals ranging from 4 h to 3 weeks. Within hours after the hypoxic-ischemic insult 20% of the total cells were deleted from the SVZ. The residual damaged cells appeared necrotic. During 48 h of recovery deaths accumulated; however, these later deaths were predominantly apoptotic. Many apoptotic SVZ cells stained with a marker for immature oligodendrocytes. At 3 weeks survival, the SVZ was smaller and markedly less cellular, and it contained less than 1/4 the normal complement of neural stem cells. The corresponding subcortical white matter was dysmyelinated, relatively devoid of oligodendrocytes and enriched in astrocytes. We conclude that neural stem cells and oligodendrocyte progenitors in the SVZ are vulnerable to hypoxia/ischemia. Consequently, the developmental production of oligodendrocytes is compromised and regeneration of damaged white matter oligodendrocytes does not occur resulting in failed regeneration of CNS myelin in periventricular loci. The resulting dysgenesis of the brain that occurs subsequent to perinatal hypoxic/ischemic injury may contribute to the cognitive and motor dysfunction that results from asphyxia of the newborn.
Levison
S W
SW
Department of Neuroscience and Anatomy, Pennsylvania State University, College of Medicine, Hershey, Pa 17033, USA. slevison@psu.edu
Rothstein
R P
RP
Romanko
M J
MJ
Snyder
M J
MJ
Meyers
R L
RL
Vannucci
S J
SJ
D000818:Animals; D017209:Apoptosis; D002547:Cerebral Palsy / Q000473:pathology; D002552:Cerebral Ventricles / Q000196:embryology* / Q000473:pathology; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D009836:Oligodendroglia / Q000473:pathology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000473:pathology*; D020521:Stroke / Q000473:pathology