Reversible effect of X-irradiation on proliferation, neurogenesis, and cell death in the dentate gyrus of adult mice

Abstract

Therapeutic cranial X-irradiation causes cognitive deficits in adult and pediatric patients, in particular, when the exposed area includes the medial temporal lobes. Effects on adult neurogenesis within the hippocampus may be related to such deficits. To investigate this relation, we irradiated the brain of young adult C57Bl/6j mice with a single dose of 4 Gy at a dose-rate of 27.5 cGy/min. We observed an approximately 80% decrease in the number of cells immunoreactive for the proliferation marker Ki67, 16 and 48 h after exposure, which was restored to control values after 1 week. The number of doublecortin- and NeuroD-immunoreactive cells of neuronal lineage was reduced by 60-70% up to 1 week after irradiation, but not after 1 month. The number of pyknotic cells increased approximately 2.5 fold after 16 h, decreased to approximately 50% of control numbers after 48 h and 1 week, and was again at normal levels after 1 month. Granule cell number did not differ between different groups and time points. There was no apparent activation of microglia or astrocytes. Our findings consist of an acute and reversible effect of X-irradiation on proliferation, neurogenesis, and cell death. Transient changes of neurogenesis may play a role in transient impairments of cognitive performance of patients exposed to X-irradiation. We present an experimental approach to temporarily alter adult hippocampal neurogenesis (AhN), allowing mechanistic investigations of AhN and its relevance to cognitive performances. The work also represents a step toward optimized radiotherapy schedules.