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Altered levels of immune cell adhesion molecules are associated with memory impairment in schizophrenia and healthy controls.

免疫细胞粘附分子水平的改变与精神分裂症和健康对照者的记忆障碍有关。

  • 影响因子:6.09
  • DOI:10.1016/j.bbi.2020.06.017
  • 作者列表:"Cai HQ","Weickert TW","Catts VS","Balzan R","Galletly C","Liu D","O'Donnell M","Shannon Weickert C
  • 发表时间:2020-06-12
Abstract

:Increased cytokines and increased intercellular adhesion molecule-1 (ICAM1) found in the schizophrenia prefrontal cortex and in the blood may relate to cognitive deficits. Endothelial ICAM1 regulates immune cell trafficking into the brain by binding to integrins located on the surface of leukocytes. Whether the circulating levels of the main ICAM1 adhesion partners, lymphocyte-function associated antigen-1 (LFA1) and complement receptor 3 (CR3), both integrins, are altered in schizophrenia is unknown. Gene expressions of ICAM1, LFA1 and CR3 were measured in leukocytes from 86 schizophrenia patients and 77 controls. Participants were also administered cognitive testing to determine the extent to which cognitive ability was related to molecular measures of leukocyte adhesion. This cohort was previously stratified into inflammatory subgroups based on circulating cytokine mRNAs; thus, gene expressions were analysed by diagnosis and by inflammatory subgroups. Previously measured plasma ICAM1 protein was elevated in "high inflammation" schizophrenia compared to both "high" and "low inflammation" controls while ICAM1 mRNA was unchanged in leukocytes. LFA1 mRNA was decreased and CR3 mRNA was increased in leukocytes from people with schizophrenia compared to controls. LFA1 mRNA levels were positively correlated with working memory and elevated soluble ICAM1 was negatively correlated with verbal memory in schizophrenia. Altogether, some of the cognitive deficits in schizophrenia may be associated with altered expression of molecules that regulate immune cell trafficking.

摘要

: 精神分裂症前额叶皮质和血液中发现的细胞因子增加和细胞间黏附分子-1 (ICAM1) 增加可能与认知缺陷有关。内皮 ICAM1 通过与位于白细胞表面的整合素结合来调节免疫细胞向大脑的运输。精神分裂症中主要的 ICAM1 粘附伴侣、淋巴细胞功能相关抗原-1 (LFA1) 和补体受体 3 (CR3) (两种整合素) 的循环水平是否发生改变尚不清楚。测定 86 例精神分裂症患者和 77 例对照者白细胞中 ICAM1 、 LFA1 和 CR3 的基因表达。参与者还进行了认知测试,以确定认知能力与白细胞粘附的分子测量相关的程度。该队列以前根据循环细胞因子 mrna 分为炎症亚组; 因此,通过诊断和炎症亚组分析基因表达。先前测量的血浆 ICAM1 蛋白在 “高炎症” 精神分裂症中与 “高炎症” 和 “低炎症” 对照相比均升高,而 ICAM1 mRNA 在白细胞中不变。与对照组相比,精神分裂症患者白细胞中 LFA1 mRNA 降低,CR3 mRNA 升高。精神分裂症患者 LFA1 mRNA 水平与工作记忆呈正相关,可溶性 ICAM1 升高与言语记忆呈负相关。总之,精神分裂症的一些认知缺陷可能与调节免疫细胞运输的分子表达改变有关。

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影响因子:9.56
发表时间:2020-01-24
来源期刊:Molecular psychiatry
DOI:10.1038/s41380-020-0649-0
作者列表:["Li C","Meng F","Garza JC","Liu J","Lei Y","Kirov SA","Guo M","Lu XY"]

METHODS::The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.

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影响因子:5.83
发表时间:2020-01-22
DOI:10.1523/JNEUROSCI.0786-19.2019
作者列表:["Torretta S","Rampino A","Basso M","Pergola G","Di Carlo P","Shin JH","Kleinman JE","Hyde TM","Weinberger DR","Masellis R","Blasi G","Pennuto M","Bertolino A"]

METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.

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影响因子:6.22
发表时间:2020-01-17
DOI:10.1038/s41386-020-0614-2
作者列表:["Chadha R","Meador-Woodruff JH"]

METHODS::Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.

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