Abstract Radiotherapy is a key treatment for high-grade brain tumors, significantly improving survival rates, especially in pediatric patients. However, it leads to long-term complications, including cognitive deficits, in 50-96 % of patients. No treatments currently exist to prevent these deficits. Lithium (Li), known for treating bipolar affective disorder, has been shown to reduce radiation-induced cognitive impairments in rodents by protecting the neuronal stem and progenitor cells in the hippocampus from apoptosis and promoting their proliferation. This study aimed to explore further the mechanisms underlying the protective and regenerative effects of Li in the irradiated young brain. To this end, postnatal day (PD) 21 C57BL6/J mice were injected intraperitoneally with Li chloride (4 mmol/kg) and kept on a Li carbonate-containing diet for 4 weeks. Control animals were injected with saline and administered an equivalent control diet. On PD 25, the animals were administered a single-dose whole-brain radiation of 8 Gy and were subsequently sacrificed at different time points, spanning from 2 weeks to 1 year. Hippocampi were collected for single-cell RNA sequencing using a novel protocol to capture viable cells, including neurons, and for electrophysiology analysis. The results showed that radiation induced the expression of the senescence genes in hippocampal microglia (e.g., Cdkn1a, Ccl12), which Li prevented. Additionally, Li also prevented the radiation-induced loss of hippocampal gamma oscillations and protected the newly generated hippocampal neurons, leading to the development of new neuronal subpopulations that prevailed in the hippocampus long after irradiation. Finally, a subpopulation of pruning microglia was shown to play a key role in Li-driven neuronal changes. This study advances our understanding of the effects of Li in the irradiated brain and supports its potential as the first pharmacological treatment for radiation-induced late complications.
Rodrigues et al. (Fri,) studied this question.