Csf1R Regulates Schizophrenia-Related Stress Response and Vascular Association of Microglia/Macrophages

Authors

Ling Yan
Yanli Li
Fengmei Fan
Mengzhuang Gou
Fangling Xuan
Wei Feng
Keerthana Chithanathan
Wei Li
Junchao Huang
Hongna Li
Wenjin Chen
Baopeng Tian
Zhiren Wang
Shuping Tan
Alexander Zharkovsky
L Elliot Hong
Yunlong Tan
Li Tian

Publication Date

8-4-2023

Journal

BMC Medicine

Abstract

BACKGROUND: Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility.

METHODS: We recruited a cohort of first episode schizophrenia (FES) patients (n = 51) and age- and sex-paired healthy controls (HCs) (n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating factor 1 receptor (CSF1R). Furthermore, we studied a mouse model of chronic unpredictable stress (CUS) combined with a CSF1R inhibitor (CSF1Ri) (n = 9 ~ 10/group) on anxiety behaviours and microglial biology.

RESULTS: FES patients showed higher scores of perceived stress scale (PSS, p < 0.05), lower blood CSF1R mRNA (FDR = 0.003) and protein (p < 0.05) levels, and smaller volumes of the superior frontal gyrus and parahippocampal gyrus (both FDR < 0.05) than HCs. In blood RNA-seq, CSF1R-associated differentially expressed blood genes were related to brain development. Importantly, CSF1R facilitated a negative association of the superior frontal gyrus with PSS (p < 0.01) in HCs but not FES patients. In mouse CUS+CSF1Ri model, similarly as CUS, CSF1Ri enhanced anxiety (both p < 0.001). Genes for brain angiogenesis and intensity of CD31

CONCLUSION: Microglial/macrophagic CSF1R regulated schizophrenia-associated stress and brain angiogenesis.

Keywords

Animals, Humans, Mice, Brain, Disease Models, Animal, Macrophages, Microglia, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Schizophrenia

DOI

10.1186/s12916-023-02959-8

PMID

37542262

PMCID

PMC10403881

PubMedCentral® Posted Date

August 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes