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Overexpression of transmembrane TNFα in brain endothelial cells induces schizophrenia-relevant behaviors

Molecular Psychiatry volume 28, pages 843–855 (2023)Cite this article

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Abstract

Upregulation of genes and coexpression networks related to immune function and inflammation have been repeatedly reported in the brain of individuals with schizophrenia. However, a causal relationship between the abnormal immune/inflammation-related gene expression and schizophrenia has not been determined. We conducted co-expression networks using publicly available RNA-seq data from prefrontal cortex (PFC) and hippocampus (HP) of 64 individuals with schizophrenia and 64 unaffected controls from the SMRI tissue collections. We identified proinflammatory cytokine, transmembrane tumor necrosis factor-α (tmTNFα), as a potential regulator in the module of co-expressed genes that we find related to the immune/inflammation response in endothelial cells (ECs) and/or microglia of the brain of individuals with schizophrenia. The immune/inflammation-related modules associated with schizophrenia and the TNF signaling pathway that regulate the network were replicated in an independent cohort of brain samples from 68 individuals with schizophrenia and 135 unaffected controls. To investigate the association between the overexpression of tmTNFα in brain ECs and schizophrenia-like behaviors, we induced short-term overexpression of the uncleavable form of (uc)-tmTNFα in ECs of mouse brain for 7 weeks. We found schizophrenia-relevant behavioral deficits in these mice, including cognitive impairment, abnormal sensorimotor gating, and sensitization to methamphetamine (METH) induced locomotor activity and METH-induced neurotransmitter levels. These uc-tmTNFα effects were mediated by TNF receptor2 (TNFR2) and induced activation of TNFR2 signaling in astrocytes and neurons. A neuronal module including neurotransmitter signaling pathways was down-regulated in the brain of mice by the short-term overexpression of the gene, while an immune/inflammation-related module was up-regulated in the brain of mice after long-term expression of 22 weeks. Our results indicate that tmTNFα may play a direct role in regulating neurotransmitter signaling pathways that contribute to the clinical features of schizophrenia.

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Fig. 1: tmTNFα is a candidate key regulator for the immune/inflammation-related co-expression modules associated with schizophrenia.
Fig. 2: A mouse model overexpressing uncleavable tmTNFα in brain endothelial cells.
Fig. 3: Over-expression of uc-tmTNFα in the EC induces schizophrenia-relevant behaviors in mice.
Fig. 4: Over-expression of uc-tmTNFα in the ECs caused deficits in neurotransmitter signaling in the PFC.
Fig. 5: The effects of tmTNFα on schizophrenia-related behaviors mediated by TNFR2 and not by TNFR1.

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Acknowledgements

We thank all the investigators who generated the RNA-Seq data and neuropathology data deposited in the SNCID (http://sncid.stanleyresearch.org). The RNA-seq data used for our replication study was obtained from dbGAP database (accession number phs000979.v2.p2). We also thank Jonathan Cohen, Kenya Platero, SignaGen Co., and Macrogen Co. for their technical assistance. Financially support was provided by the National Research Foundation of Korea [NRF] Grant funded by the Korea government (MSIP) (No. MRC, 2017R1A5A2015541). The authors declare that they have no conflict of interest. The RNA-Seq raw data (FASTQ) files are publicly available for download at http://sncid.stanleyresearch.org (SNCID).

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  1. These authors contributed equally: In Jun Yeo, Jaesuk Yun.

Authors and Affiliations

  1. College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 28160, Republic of Korea

    In Jun Yeo, Jaesuk Yun, Dong Ju Son, Sang-Bae Han & Jin Tae Hong

  2. Stanley Brain Research Laboratory, Stanley Medical Research Institute, 9800 Medical Center Drive, Rockville, MD, 20850, USA

    Maree J. Webster & Sanghyeon Kim

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Contributions

IJY, JY, JTH, and SK designed the study. MJW and SK performed the human post-mortem study and analysis of the data. IJY, JY, DJS, SH, and JTH performed the animal experiments and statistical analysis of the mouse behavioral data. IJY, JY, MJW, and SK drafted the manuscript, and JTH, MJW, and SK revised it. All authors reviewed and approved the final version.

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Correspondence to Jin Tae Hong or Sanghyeon Kim.

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Yeo, I.J., Yun, J., Son, D.J. et al. Overexpression of transmembrane TNFα in brain endothelial cells induces schizophrenia-relevant behaviors. Mol Psychiatry 28, 843–855 (2023). https://doi.org/10.1038/s41380-022-01846-7

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