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Differential profiles of response inhibition deficit between male children with autism spectrum disorders and schizophrenia.


  • 影响因子:3.94
  • DOI:10.1002/aur.2231
  • 作者列表:"Shi LJ","Zhou HY","Shen YM","Wang Y","Fang YM","He YQ","Ou JJ","Luo XR","Cheung EFC","Chan RCK
  • 发表时间:2020-04-01

:Autism spectrum disorders (ASD) and schizophrenia (SZ) are both associated with response inhibition impairment. However, the relative pattern of deficits in these two disorders remains unclear. Twenty-three male children with ASD, 23 male children with SZ, and 32 typically developing male controls were recruited to complete a set of tasks measuring response inhibition in the visual, auditory, and verbal domains. We found that visual, auditory, and verbal response inhibitions were impaired in both children with ASD and children with SZ. Compared with typically developing controls, children with ASD made more commission errors whereas children with SZ responded much slower in the visual response inhibition task. Both clinical groups showed comparable impairment in verbal response inhibition, but children with SZ were more impaired in auditory response inhibition than children with ASD. These different patterns of response inhibition deficit between male children with ASD and SZ may help to differentiate between these two disorders and may be potential targets for intervention. Autism Res 2020, 13: 591-602. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In this study, we found that male children with autism spectrum disorder (ASD) made more commission errors whereas male children with schizophrenia (SZ) responded much slower in the visual response inhibition task. Both clinical groups exhibited comparable impairments in verbal response inhibition, but male children with SZ were more impaired in auditory response inhibition than male children with ASD. Our findings provide potential targets for intervention.


: 自闭症谱系障碍 (ASD) 和精神分裂症 (SZ) 均与反应抑制障碍有关。然而,这两种疾病的相对缺陷模式仍不清楚。招募了 23 名 ASD 男性儿童、 23 名 SZ 男性儿童和 32 名典型发育中的男性对照,以完成一组测量视觉、听觉、和言语领域。我们发现 ASD 儿童和 SZ 儿童的视觉、听觉和言语反应抑制均受损。与典型发育中的对照相比,ASD 儿童犯了更多的委员会错误,而 SZ 儿童在视觉反应抑制任务中的反应要慢得多。两个临床组在言语反应抑制方面均表现出相当的损害,但 SZ 患儿在听觉反应抑制方面较 ASD 患儿受损更多。ASD 和 SZ 男性儿童反应抑制缺陷的这些不同模式可能有助于区分这两种疾病,并可能是干预的潜在靶点。自闭症 Res 2020,13: 591-602。©2019 国际自闭症研究学会,Wiley 期刊,Inc. LAY 总结: 在这项研究中,我们发现患有自闭症谱系障碍 (ASD) 的男性儿童犯了更多的委员会错误,而患有精神分裂症的男性儿童 (SZ) 在视觉反应抑制任务中反应慢得多。两个临床组在言语反应抑制方面表现出相当的损伤,但男性 SZ 患儿在听觉反应抑制方面比男性 ASD 患儿受损更多。我们的发现为干预提供了潜在的靶点。



来源期刊:Molecular psychiatry
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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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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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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