A large number of brain tumor patients are treated with brain irradiation every year. Nowadays patients tend to have longer survival after diagnosis, however, are more likely to suffer from radiotherapy-induced cognitive decline. We have previously demonstrated that temporary microglia depletion is able to prevent brain radiotherapy-induced memory loss in a new mouse glioblastoma model. This result suggests that the activation of microglia is essential for the development of cognitive deficits after brain radiotherapy. We are currently investigating the molecular signals in microglia that induces neuronal dysfunctions and cognitive deficits, and exploring new therapeutic targets.