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

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

  • Acta Neuropathol Commun. 2025 May 19;13(1):105. doi: 10.1186/s40478-025-02026-8.
Yubo Hu # 1 2 3 4,  Zhe Li # 2 3 4,  Yafeng Zhu # 5,  Mengdan Xing 5 6 7 8,  Xiaoru Xie 5 6 8,  Panwu Zhao 2 3 4,  Xin Cheng 2 3 4,  Chuan Xiao 2 3 4,  Yuting Xia 6,  Jingru Wu 6,  Yuan Luo 6,  Ho Ko 9 10 11 12 13 14 15 16,  Yamei Tang 17 18 19 20,  Xiaojing Ye 21 22 23,  Wei-Jye Lin 24 25 26 27
Affiliations

Affiliations

  • 1 Medical College of Jiaying University, Meizhou, Guangdong, 514031, China.
  • 2 Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 3 Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 4 Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 5 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
  • 6 Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
  • 7 Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
  • 8 Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China.
  • 9 Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, SAR, Hong Kong, China.
  • 10 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, SAR, Hong Kong, China.
  • 11 Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, SAR, Hong Kong, China.
  • 12 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, SAR, Hong Kong, China.
  • 13 Gerald Choa Neuroscience Center, The Chinese University of Hong Kong, SAR, Hong Kong, China.
  • 14 Margaret K. L. Cheung Research Centre for Management of Parkinsonism, Faculty of Medicine, The Chinese University of Hong Kong, SAR, Hong Kong, China.
  • 15 Chow Yuk Ho Technology Center for Innovative Medicine, The Chinese University of Hong Kong, SAR, Hong Kong, China.
  • 16 Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong, SAR, Hong Kong, China.
  • 17 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China. tangym@mail.sysu.edu.cn.
  • 18 Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. tangym@mail.sysu.edu.cn.
  • 19 Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. tangym@mail.sysu.edu.cn.
  • 20 Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China. tangym@mail.sysu.edu.cn.
  • 21 Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. yexiaoj8@mail.sysu.edu.cn.
  • 22 Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. yexiaoj8@mail.sysu.edu.cn.
  • 23 Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. yexiaoj8@mail.sysu.edu.cn.
  • 24 Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. linwj26@mail.sysu.edu.cn.
  • 25 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China. linwj26@mail.sysu.edu.cn.
  • 26 Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. linwj26@mail.sysu.edu.cn.
  • 27 Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China. linwj26@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40390112 DOI: 10.1186/s40478-025-02026-8
Abstract

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.

Keywords

Leukotriene-C4; Medial prefrontal cortex; Microglia; Neuroinflammation; Radiation-induced brain injury.

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