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The Journal of Neuroscience, November 24, 2004, 24(47):10763-10772; doi:10.1523/JNEUROSCI.3883-04.2004

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Neurobiology of Disease
Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

Chia-Yi Kuan,¹ Aryn J. Schloemer,¹ Aigang Lu,³ Kevin A. Burns,¹ Wei-Lan Weng,¹ Michael T. Williams,² Kenneth I. Strauss,⁴ Charles V. Vorhees,¹ Richard A. Flavell,⁵ Roger J. Davis,⁷ Frank R. Sharp,³ and Pasko Rakic⁶

Department of Pediatrics, Divisions of ¹Developmental Biology and ²Neurology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, Departments of ³Neurology and ⁴Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, ⁵Howard Hughes Medical Institute and Section of Immunobiology and ⁶Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, and ⁷Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Recent studies suggest that postmitotic neurons can reenter the cell cycle as a prelude to apoptosis after brain injury. However, most dying neurons do not pass the G₁/S-phase checkpoint to resume DNA synthesis. The specific factors that trigger abortive DNA synthesis are not characterized. Here we show that the combination of hypoxia and ischemia induces adult rodent neurons to resume DNA synthesis as indicated by incorporation of bromodeoxyuridine (BrdU) and expression of G₁/S-phase cell cycle transition markers. After hypoxia-ischemia, the majority of BrdU- and neuronal nuclei (NeuN)-immunoreactive cells are also terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-stained, suggesting that they undergo apoptosis. BrdU⁺ neurons, labeled shortly after hypoxia-ischemia, persist for >5 d but eventually disappear by 28 d. Before disappearing, these BrdU⁺/NeuN⁺/TUNEL⁺ neurons express the proliferating cell marker Ki67, lose the G₁-phase cyclin-dependent kinase (CDK) inhibitors p16INK4 and p27Kip1 and show induction of the late G₁/S-phase CDK2 activity and phosphorylation of the retinoblastoma protein. This contrasts to kainic acid excitotoxicity and traumatic brain injury, which produce TUNEL-positive neurons without evidence of DNA synthesis or G₁/S-phase cell cycle transition. These findings suggest that hypoxia-ischemia triggers neurons to reenter the cell cycle and resume apoptosis-associated DNA synthesis in brain. Our data also suggest that the demonstration of neurogenesis after brain injury requires not only BrdU uptake and mature neuronal markers but also evidence showing absence of apoptotic markers. Manipulating the aberrant apoptosis-associated DNA synthesis that occurs with hypoxia-ischemia and perhaps neurodegenerative diseases could promote neuronal survival and neurogenesis.

Key words: neurogenesis; apoptosis; cell cycle; BrdU; ischemia; hypoxia

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Received March 22, 2004; revised October 12, 2004; accepted October 14, 2004.

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