Cranial radiotherapy is a standard treatment for brain tumours, but is associated with late side effects including compromised cognitive functions that can significantly impair patients’ quality of life. Cognitive impairment is a major dose-limiting factor for cranial radiotherapy, and has therefore been an important subject of study. A large body of preclinical studies suggest that injury to the hippocampus, a key structure for learning and memory, contributes to radiation-induced cognitive impairment. Hippocampus houses the life-long generation of new neurons, a process termed neurogenesis. Neurogenesis inhibition is considered to be one of the most important mechanisms leading to post-irradiation cognitive impairment. Mechanistic insights into how radiation affects neurogenesis could therefore help to alleviate the undesirable effects from cranial radiotherapy.
I postulate that p53, an extensively studied tumor suppressor known to play an important role in both radiation biology and stem cell biology, regulates post-irradiation neurogenesis. The role of p53 in post-irradiation hippocampal neurogenesis was examined using transgenic mice with different copy numbers of the p53 gene. We also examined the effects of aging on post-irradiation hippocampal neurogenesis because of the reported age-dependent increase of p53 in the hippocampus. The impact of cranial irradiation on hippocampus was further evaluated using a set of endpoints characterizing cellular senescence to complement limitations associated with neurogenesis endpoints.
We showed for the first time that p53 deficiency exacerbated the disruption of hippocampal neuronal development after irradiation in adult mouse brain (Chapter 3). This profound post-irradiation neurogenesis inhibition was associated with increased neural stem cell activation and the depletion of neuronal stem cell pool. Although p53 has been shown to increase with aging in the hippocampus, cranial irradiation was found to further inhibit the age-dependent decrease in hippocampal neurogenesis (Chapter 4). Cranial irradiation resulted in increased expression of senescence markers in mouse dentate gyrus (Chapter 5). Ablation of p53 may alter radiation-induced cellular senescence in the hippocampus, although further investigations are needed to determine the functional significance of this finding. These investigations provide mechanistic insight into the effects of cranial irradiation on hippocampal neuronal development and the pathophysiology of cognitive impairment after cranial irradiation.Ph.D
