CSF1R Contributes to Vascular Association of Microglia and Stress Regulation in Schizophrenia

Abstract Whether and how microglia contribute to stress and anxiety in schizophrenia are not well established. We hypothesized that microglial colony stimulating factor 1 receptor (CSF1R) regulates stress susceptibility in schizophrenia via the hippocampus and associated cortical regions. A cohort of first-episode schizophrenia (FES) patients (n=51) and age- and sex-paired healthy controls (HCs) (n=46) were first recruited. Compared to HCs, FES patients showed higher scores of perceived stress scale (PSS, p<0.01), lower levels of CSF1R mRNA (Log2FC=-0.195, FDR=0.003) and protein (18.31±0.95 vs. 20.49±0.90 µg/ml, p<0.05) in the blood, and smaller volumes of the superiorfrontal gyrus (39.13±0.64 vs. 40.80±0.76 cm3, FDR<0.05) and parahippocampal gyrus (3.51±0.048 vs. 3.72±0.058 cm3, FDR<0.05). CSF1R facilitated the negative superiorfrontal gyral association with PSS (β=6.109, 95% CI: 1.642~10.578, p<0.01) in HCs but not FES patients. CSF1R-associated gene network contributed to brain development. We further studied a chronic unpredictable stress (CUS) mouse model combined with a CSF1R inhibitor (CSF1Ri). Both CUS and CSF1Ri enhanced anxiety in mice (both p<0.001). RNA-seq revealed downregulation of genes for cell adhesion and angiogenesis after CUS-CSF1Ri treatment. Immunostaining showed downregulation of CD31 and preferential loss of vessel-associated IBA1+-microglia induced by CUS or CSF1Ri (p<0.05). Oligodendrocyte precursor cells were however increased after CUS-CSF1Ri treatment (p<0.01). These results suggest that microglial CSF1R showed a protective effect on stress and anxiety in FES patients and CUS mice via contribution to angiogenesis.