Replenished microglia partially rescue schizophrenia-related stress response

Frontiers in Cellular Neuroscience

Cellular Neuroscience

Alexander Zharkovsky¹  Fang-Ling Xuan¹  Ling Yan¹  Li Tian²  Fengmei Fan³  Zhiren Wang³  Leilei Wang³  Mengzhuang Gou³  Song Chen³  Ting Xie³  Yanli Li³  Wenjin Chen³  Yunlong Tan³ 

[1] Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia;Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia;Psychiatry Research Centre, Beijing Huilongguan Hospital, Peking University Health Science Center, Beijing, China;Psychiatry Research Centre, Beijing Huilongguan Hospital, Peking University Health Science Center, Beijing, China;

关键词: microglial replenishment;    synaptic pruning;    prefrontal cortex;    hippocampus;    chronic unpredictable stress;    schizophrenia;   

DOI  :  10.3389/fncel.2023.1254923

 received in 2023-07-07, accepted in 2023-08-15,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundMicroglia play an important role in the maintenance of brain and behavioral homeostasis. The protective effect of microglial replenishment was reported in neurological diseases, but whether microglial therapy would benefit psychiatric disorders such as schizophrenia has been unclear. As schizophrenia is a stress-vulnerable disorder and psychosocial stress promotes inflammation and microglial activation, we aim to understand how microglial replenishment works in stress-associated schizophrenia.MethodsWe used a CSF1R-mediated pharmacological approach to study repopulated microglia (repMg) in a cohort of mice (n = 10/group) undergoing chronic unpredictable stress (CUS). We further studied a cohort of first-episode schizophrenia (FES, n = 74) patients who had higher perceived stress scores (PSS) than healthy controls (HCs, n = 68).ResultsReborn microglia attenuated CUS-induced learned hopelessness and social withdrawal but not anxiety in mice. Compared to control, CUS- or repMg-induced differentially expressed genes (DEGs) in the prefrontal cortex regulated nervous system development and axonal guidance. CUS also caused microglial hyper-ramification and increased engulfment of synaptophysin and vesicular glutamate transporter-2 by microglia and astrocytes, which were recovered in CUS + repMg (all p < 0.05). Moreover, FES patients had smaller hippocampal fimbria than HCs (p < 1e-7), which were negatively associated with PSS (r = −0.397, p = 0.003). Blood DEGs involved in immune system development were also associated with PSS and the right fimbria more prominently in FES patients than HCs (Zr, p < 0.0001). The KCNQ1 was a partial mediator between PSS and fimbria size (β = −0.442, 95% CI: −1.326 ~ −0.087).ConclusionMicroglial replenishment may potentially benefit psychiatric disorders such as schizophrenia.

【 授权许可】

Unknown   
Copyright © 2023 Yan, Xuan, Chen, Gou, Chen, Li, Wang, Wang, Xie, Fan, Zharkovsky, Tan and Tian.