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

TITLE=Replenished microglia partially rescue schizophrenia-related stress response

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=17

YEAR=2023

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2023.1254923

DOI=10.3389/fncel.2023.1254923

ISSN=1662-5102

ABSTRACT=<sec id="sec1"><title>Background</title><p>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.</p></sec><sec id="sec2"><title>Methods</title><p>We used a CSF1R-mediated pharmacological approach to study repopulated microglia (repMg) in a cohort of mice (<italic>n =</italic> 10/group) undergoing chronic unpredictable stress (CUS). We further studied a cohort of first-episode schizophrenia (FES, <italic>n =</italic> 74) patients who had higher perceived stress scores (PSS) than healthy controls (HCs, <italic>n =</italic> 68).</p></sec><sec id="sec3"><title>Results</title><p>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 <italic>p</italic> &lt; 0.05). Moreover, FES patients had smaller hippocampal fimbria than HCs (<italic>p</italic> &lt; 1e-7), which were negatively associated with PSS (<italic>r</italic> = −0.397, <italic>p</italic> = 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, <italic>p</italic> &lt; 0.0001). The <italic>KCNQ1</italic> was a partial mediator between PSS and fimbria size (<italic>β</italic> = −0.442, 95% CI: −1.326 ~ −0.087).</p></sec><sec id="sec4"><title>Conclusion</title><p>Microglial replenishment may potentially benefit psychiatric disorders such as schizophrenia.</p></sec>