Lithium treatment reverses irradiation-induced changes in rodent neural progenitors

Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context, and we previously showed that voluntary running introduced long after irradiation rescued hippocampal neurogenesis in young mice (Naylor et al. 2008a). Lithium, a well-known mood stabilizer, has both neuroprotective, proneurogenic as well as anti-tumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation, analogous to the voluntary running study. Female mice received a single 4 Gy whole-brain irradiation dose at postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed at PND 77, 91 and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors and promoted neuronal integration upon its discontinuation. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with proliferation, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced impairment of hippocampal neurogenesis even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.