Microglial Deletion and Inhibition Alleviate Behavior of Post-Traumatic Stress Disorder in Mice

Abstract Background: Alteration of immune status in the central nervous system (CNS) has been implicated in the development of Post-Traumatic Stress Disorder (PTSD). However, the nature of overall changes in brain immunocyte landscape in PTSD condition remains unclear. Methods: We constructed a mouse PTSD model by electric foot-shocks followed by contextual reminders and verified the PTSD-related symptoms by behavior test (including contextual freezing test, open filed test and elevated plus maze test). We examined the immunocyte panorama in the brains of the naïve or PTSD mice by using single cell mass cytometry. Microglia number and morphological changes in hippocampus, prefrontal cortex and amygdala were analyzed by histopathological methods. The gene expression changes of those microglia were detected by quantitative real-time PCR. Genetic/pharmacological depletion of microglia or minocycline treatment before foot-shock exposure were performed to study the role of microglia in the PTSD development and progress. Results: We found microglia are the major brain immune cells respond to PTSD. The number of microglia and ratio of microglia to immunocytes was significantly increased on the fifth day of foot-shock exposure. Furthermore, morphological analysis and gene expression profiling revealed temporal patterns of microglial activation in the hippocampus of PTSD brains. Importantly, we found that genetic/pharmacological depletion of microglia or minocycline treatment before foot-shock exposure alleviated PTSD-associated anxiety and contextual fear. Conclusion: Our results demonstrated a critical role for microglial activation in PTSD development and a potential therapeutic strategy for the clinical treatment of PTSD in the form of microglial inhibition.