Microglial repopulation reverses radiation-induced cognitive dysfunction by restoring medial prefrontal cortex activity and modulating leukotriene-C4 synthesis.

Cranial radiotherapy and environmental radiation exposure are associated with increased risk of cognitive dysfunction, including memory deficits and mood disorders, yet the underlying mechanisms remain poorly understood. In this study, we demonstrate that cranial irradiation induces hypoactivity in the medial prefrontal cortex (mPFC) of mice, leading to anxiety-like behaviors and memory impairments, which can be prevented by optogenetic activation of mPFC excitatory neurons. Radiaiton exposure also causes a significant reduction in microglial density within the mPFC, accompanied by morphological and transcriptional alterations in the remaining microglia. Notably, microglial repopulation, achieved through CSF1R antagonist-mediated depletion prior to irradiation and subsequent repopulation, restores mPFC neuronal acitivity and reverses cognitive and behavioral deficits. Integrated bulk RNA sequencing and microglial proteomic analysis of the mPFC reveal that microglial repopulation specifically modulates the leukotriene-C4 biosynthesis pathway, without significant changes in canonical pro-inflammatory cytokines or chemokines. Importantly, pharmacological inhibition of leukotriene-C4 synthase ameliorates radiation-induced anxiety and memory impairments. These findings identify leukotriene-C4 signaling as a critical mechanism underlying radiation-induced cognitive dysfunction and suggest that microglial repopulation and targted inhibition of leukotriene-C4 represent potential therapeutic strategies for mitigating radiation-associated cognitive disorders.