In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.
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We thank W. Stallcup for the NG2 antibody; B.E. Hoyte for help with the manuscript graphics; R. Malenka for the use of the Pritzker Foundation confocal microscope; D. Morhardt and D. Schaal for help in preparing the manuscript; and M. Brown, L. Fajardo and P. Fisher for valuable insights. This work was supported by grants MH20016-05 from the National Institute of Mental Health, R01CA76141 from the National Cancer Institute, R21NS40088 from the National Institute for Neurological Disorders and Stroke and Palmer Lab Startup funds from the Department of Neurosurgery, Stanford University.
The authors declare no competing financial interests.
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Monje, M., Mizumatsu, S., Fike, J. et al. Irradiation induces neural precursor-cell dysfunction. Nat Med 8, 955–962 (2002). https://doi.org/10.1038/nm749
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