Abstract
Radiotherapy is essential in the treatment of high-grade brain tumors. While often lifesaving, it typically results in long-term complications in 50-96 % of the treated individuals, where cognitive deficits are particularly debilitating, especially in pediatric patients. Although the survival rates have improved dramatically, there are currently no treatments or preventive strategies available to ameliorate the late cognitive complications. Lithium (Li), long used to treat patients with bipolar affective disorders, has been shown to reduce irradiation-induced cognitive deficits in rodent models by preventing apoptosis of the neuronal stem and progenitor cells in the hippocampus and stimulating their division. However, except for these anti-apoptotic and pro-neurogenic effects, there is limited understanding of how Li exerts its actions in the brain. This work aimed to further elucidate the mechanisms behind the protective action of Li in the irradiated young brain. To this end, post-natal day (PD) 21 C57BL6/J mice were intraperitoneally injected with lithium chloride (4 mmol/kg) and subsequently kept on a Li carbonate diet for 4 weeks. Control animals were injected with saline and administered an equivalent control diet. At PD25, the animals were subjected to a single dose of 8 Gy whole brain irradiation, and 6 weeks after irradiation, they were sacrificed, and their hippocampi were harvested for single-cell RNA sequencing and RT-qPCR. The attained results showed that irradiation induced hippocampal microglia senescence, as judged by the increased expression of the senescence-associated genes Cdkn1a, Cdkn2, Ccl12, C/Ebp and others in this cellular population. Conversely, Li prevented microglia senescence by activating the Bcl2 family of genes, as confirmed by the lower expression of the abovementioned senescence-associated genes in the Li-treated animals. These results provide the first step towards understanding the action of Li in the brain and confirm its potential to become the first pharmacological treatment for irradiation-induced late cognitive effects.