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  3. CSF1R regulates schizophrenia-related stress response and vascular association of microglia/macrophages

CSF1R regulates schizophrenia-related stress response and vascular association of microglia/macrophages

  • BMC Med. 2023 Aug 4;21(1):286. doi: 10.1186/s12916-023-02959-8.
Ling Yan # 1,  Yanli Li # 2,  Fengmei Fan 2,  Mengzhuang Gou 2,  Fangling Xuan 1,  Wei Feng 2,  Keerthana Chithanathan 1,  Wei Li 2,  Junchao Huang 2,  Hongna Li 2,  Wenjin Chen 2,  Baopeng Tian 2,  Zhiren Wang 2,  Shuping Tan 2,  Alexander Zharkovsky 1,  L Elliot Hong 3,  Yunlong Tan 4,  Li Tian 5 6
Affiliations

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, Peking University HuiLongGuan Clinical Medical School, Beijing, P. R. China.
  • 3 Department of Psychiatry, School of Medicine, Maryland Psychiatric Research Center, University of Maryland, Baltimore, USA.
  • 4 Psychiatry Research Centre, Beijing Huilongguan Hospital, Peking University Health Science Center, Peking University HuiLongGuan Clinical Medical School, Beijing, P. R. China. yltan21@126.com.
  • 5 Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia. li.tian@ut.ee.
  • 6 Psychiatry Research Centre, Beijing Huilongguan Hospital, Peking University Health Science Center, Peking University HuiLongGuan Clinical Medical School, Beijing, P. R. China. li.tian@ut.ee.
  • # Contributed equally.
PMID: 37542262 DOI: 10.1186/s12916-023-02959-8
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+-blood vessels were dampened after CUS-CSF1Ri treatment. Furthermore, CSF1Ri preferentially diminished juxta-vascular microglia/macrophages and induced microglia/macrophages morphological changes (all p < 0.05).

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

Keywords

Angiogenesis; Anxiety; CSF1R; First episode schizophrenia; Microglia/Brain macrophages; Stress.

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