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.
Stanley Brain Research Laboratory, Stanley Medical Research Institute, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
Mol Psychiatry. 2023 Feb;28(2):843-855. doi: 10.1038/s41380-022-01846-7. Epub 2022 Nov 4.
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.
上调与免疫功能和炎症相关的基因和共表达网络在精神分裂症患者的大脑中反复报道。然而，异常的免疫/炎症相关基因表达与精神分裂症之间的因果关系尚未确定。我们使用来自 SMRI 组织收集的 64 名精神分裂症患者和 64 名未受影响的对照者的前额叶皮层（PFC）和海马体（HP）的公开可用 RNA-seq 数据进行了共表达网络分析。我们鉴定了促炎细胞因子跨膜肿瘤坏死因子-α（tmTNFα），作为我们在与精神分裂症患者大脑中的内皮细胞（EC）和/或小胶质细胞的免疫/炎症反应相关的共表达基因模块中的潜在调节剂。与精神分裂症相关的免疫/炎症相关模块和调节该网络的 TNF 信号通路在来自 68 名精神分裂症患者和 135 名未受影响的对照者的脑样本的独立队列中得到了复制。为了研究脑 EC 中 tmTNFα的过表达与精神分裂症样行为之间的关联，我们在小鼠脑 EC 中诱导了未切割形式（uc）-tmTNFα的短期过表达，持续了 7 周。我们在这些小鼠中发现了与精神分裂症相关的行为缺陷，包括认知障碍、感觉运动门控异常以及对甲基苯丙胺（METH）诱导的运动活动和 METH 诱导的神经递质水平的敏感性增加。这些 uc-tmTNFα 效应是通过 TNF 受体 2（TNFR2）介导的，并且在星形胶质细胞和神经元中诱导了 TNFR2 信号的激活。在通过基因的短期过表达后，包括神经递质信号通路在内的神经元模块在小鼠脑中下调，而在 22 周的长期表达后，在小鼠脑中上调了与免疫/炎症相关的模块。我们的结果表明，tmTNFα 可能在调节神经递质信号通路中发挥直接作用，这些通路有助于精神分裂症的临床特征。
