Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia.
Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia.
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DOI：
10.1038/npp.2013.38
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发表时间：
2013-07
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影响因子：
--
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中科院分区：
文献类型：
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Schnurri - 2（Shn - 2）是一种核因子 - κB位点结合蛋白，它紧密结合主要组织相容性复合体I类基因和炎性细胞因子的增强子，这些基因和细胞因子已被证明具有与精神分裂症相关的常见单核苷酸多态性变异。尽管与免疫相关的基因与精神分裂症有关，但尚无研究表明它们的突变或基因敲除（KO）会导致精神分裂症。在此，我们发现Shn - 2基因敲除小鼠具有类似于精神分裂症患者的行为异常。突变小鼠的大脑表现出多种与精神分裂症相关的表型，包括与精神分裂症患者死后相似的转录组/蛋白质组变化、小白蛋白和谷氨酸脱羧酶67（GAD67）水平降低、脑电图上的θ波功率增加以及皮质变薄。齿状回颗粒细胞在突变体中未能成熟，这是先前提出的精神分裂症的一种内表型。Shn - 2基因敲除小鼠还表现出脑部轻度慢性炎症，这可由炎症标志物（包括胶质纤维酸性蛋白（GFAP）和NADH/NADPH氧化酶p22亚基（p22phox））增加以及与多种炎症情况相似的全基因组基因表达模式所证明。长期给予抗炎药物可降低Shn - 2基因敲除小鼠海马中的GFAP表达，并逆转其工作记忆和筑巢行为的缺陷。这些结果表明，免疫系统的基因诱导变化可能是精神分裂症的一个诱发因素。
Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia.
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影响因子：
3.7
作者：
Dugan LL;Ali SS;Shekhtman G;Roberts AJ;Lucero J;Quick KL;Behrens MM
通讯作者：
Behrens MM
DOI：
10.1007/7854_2010_42
发表时间：
2010-01-01
期刊：
BEHAVIORAL NEUROBIOLOGY OF SCHIZOPHRENIA AND ITS TREATMENT
影响因子：
--
作者：
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通讯作者：
Gur, Ruben C.
影响因子：
2.7
作者：
Fukuda, S;Yamasaki, Y;Hayashi, K
通讯作者：
Hayashi, K
影响因子：
6.6
作者：
Braff, David L.;Freedman, Robert;Gottesman, Irving I.
通讯作者：
Gottesman, Irving I.
影响因子：
2.5
作者：
Bayer, TA;Buslei, R;Falkai, P
通讯作者：
Falkai, P