Therapeutic doses of cranial irradiation induce hippocampus-dependent cognitive deficits in young mice

Fractionated cranial irradiation is an essential part of treatment in the management of cohorts of pediatric brain tumor and leukemia patients. Ionizing radiation damages normal brain parenchyma through a variety of poorly understood mechanisms and results in cognitive dysfunction and significant life-long disability. The goal of our study was to establish and characterize a mouse model of radiation-induced damage to the developing nervous system. Male C57BL/6 mice were exposed to a total dose of 20 Gy of fractionated cranial irradiation at 1 month of age to assess the early and late effects of clinically relevant irradiation doses on the young mouse brain. Compared to age-matched controls, an acute and prolonged decrease in proliferation and the number of immature neurons in the stem cell niche of the hippocampal subgranular zone within the dentate gyrus at 72 h and 1 month following cranial irradiation was noted. Behavioral characterization at 1 and 5 months post-radiation demonstrated significant, persistent and progressive hippocampus-dependent learning deficits. Our study characterizes a clinically relevant mouse model of radiation-induced damage that serves as a platform for future evaluation of therapeutic interventions that may mitigate such cognitive damage. Our research also emphasizes the need for targeted treatment strategies that protect regions of neurogenesis while maximizing therapeutic effects in pediatric cancer patients.