Replenished microglia partially rescue schizophrenia-related stress response

Ling Yan; Fang-Ling Xuan; Song Chen; Mengzhuang Gou; Wenjin Chen; Yanli Li; Zhiren Wang; Leilei Wang; Ting Xie; Fengmei Fan; Alexander Zharkovsky; Yunlong Tan; Li Tian

doi:10.3389/fncel.2023.1254923

Replenished microglia partially rescue schizophrenia-related stress response

Front Cell Neurosci. 2023 Sep 12:17:1254923. doi: 10.3389/fncel.2023.1254923. eCollection 2023.

Authors

Ling Yan¹, Fang-Ling Xuan¹, Song Chen², Mengzhuang Gou², Wenjin Chen², Yanli Li², Zhiren Wang², Leilei Wang², Ting Xie², Fengmei Fan², Alexander Zharkovsky¹, Yunlong Tan², Li Tian^{1

2}

Affiliations

¹ Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia.
² Psychiatry Research Centre, Beijing Huilongguan Hospital, Peking University Health Science Center, Beijing, China.

Abstract

Background: Microglia 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.

Methods: We 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).

Results: Reborn 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).

Conclusion: Microglial replenishment may potentially benefit psychiatric disorders such as schizophrenia.

Keywords: chronic unpredictable stress; hippocampus; microglial replenishment; prefrontal cortex; schizophrenia; synaptic pruning.