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Lack of interferon regulatory factor 3 leads to anxiety/depression-like behaviors through disrupting the balance of neuronal excitation and inhibition in mice

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Genes & Diseases 2023年第3期10卷 1062-1074页

作者： Junjie Li Yayan Pang Yehong Du Lei Xia Mulan Chen Yepeng Fan Zhifang Dong Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChina International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren's Hospital of Chongqing Medical UniversityChongqing 400014China

Disrupting the balance of neuronal excitation and inhibition (E/I) is an important pathogenic mechanism of anxiety and depression. Interferon regulatory factor 3 (IRF3) plays a key role in the innate immune response, and activation of IRF3 triggers the expression of type I interferons and downstream interferon-stimulated genes, which are associated with anxiety and depression. However, whether IRF3 participates in the pathogenesis of anxiety/depression by regulating E/I balance remains poorly understood. Here, we reported that global knockout (KO) of IRF3 (IRF3^(−/−)) significantly increased anxiety/depression-like behaviors, but did not affect normal spatial learning and memory. Compared with wild type (WT) control mice, the E/I balance was disrupted, as reflected by enhanced glutamatergic transmission and decreased GABAergic transmission in the neurons of hippocampal CA1 and medial prefrontal cortex (mPFC) in IRF3-KO mice. Importantly, genetic rescue of IRF3 expression by adeno-associated virus (AAV) was sufficient to alleviate anxiety/depression-like behaviors and restore the neuronal E/I balance in IRF3-KO mice. Taken together, our results indicate that IRF3 is critical in maintaining neuronal E/I balance, thereby playing an essential role in ensuring emotional stability.

关键词： Anxiety Depression Hippocampus IRF3 Medial prefr ontal cortex Synaptic transmission

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miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1- containing AMPA receptors in a mouse model of Alzheimer’s disease

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Acta Pharmaceutica Sinica B 2024年第2期14卷 635-652页

作者： Man Luo Yayan Pang Junjie Li Lilin Yi Bin Wu Qiuyun Tian Yan He Maoju Wang Lei Xia Guiqiong He Weihong Song Yehong Du Zhifang Dong Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChina International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing 400014China Department of Anatomy Basic Medical CollegeChongqing Medical UniversityChongqing 400016China Townsend Family Laboratories Department of PsychiatryThe University of British ColumbiaVancouver BC V6T 1Z3Canada Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Institute of AgingKey Laboratory of Alzheimer’s Disease of Zhejiang ProvinceZhejiang Clinical Research Center for Mental DisordersSchool of Mental Health and the Affiliated Kangning HospitalWenzhou Medical UniversityWenzhou 325000China Institute for Brain Science and Disease of Chongqing Medical University Chongqing 400016China

Alzheimer ’s disease(AD) is a leading cause of dementia in the elderly.Mitogen-activated protein kinase phosphatase 1(MKP-1) plays a neuroprotective role in AD.However,the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied.MicroRNAs(miRNAs) regulate gene expression at the post-transcriptional level,thereby repressing mRNA translation.Here,we reported that the microRNA-429-3p(miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPPAD model cells.We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3’-untranslated region(3’ UTR).Inhibition of miR-429-3p by its antagomir(A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation.More importantly,intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase(ERK1/2)-mediated GluAl hyperphosphorylation at Ser831 site,thereby increasing the surface expression of GluAl-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors(AMPARs).Together,these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice,suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

关键词： Alzheimer's disease MKP-1 miR-429-3p AMPAreceptor Learning and memory Long-term potentiation

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MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models

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Signal Transduction and Targeted Therapy 2019年第1期4卷 149-160页

作者： Yehong Du Yexiang Du Yun Zhang Zhilin Huang Min Fu Junjie Li Yayan Pang Peng Lei Yu Tian Wang Weihong Song Guiqiong He Zhifang Dong Pediatric Research Institute Ministry of Education Key Laboratory of Child Development and DisordersNational Clinical Research Center for Child Health and DisordersChina International Science and Technology Cooperation Base of Child Development and Critical DisordersChongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory DisordersChildren’s Hospital of Chongqing Medical UniversityChongqing400014PR China Department of Anatomy Basic Medical CollegeChongqing Medical UniversityChongqing400016PR China Townsend Family Laboratories Department of PsychiatryThe University of British ColumbiaVancouverBCV6T 1Z3Canada West China School of Basic Medical Sciences and Forensic Medicine Sichuan UniversityChengdu610041SichuanChina Brain Research Centre The University of British ColumbiaVancouverBCV6T 2B5Canada

Mitogen-activated protein kinase(MAPK)phosphatase 1(MKP-1)is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues.Dysregulation of the MAPK signaling pathway has been associated with Alzheimer’s disease(AD).However,the role of MKP-1 in AD pathogenesis remains elusive.Here,we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model.The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1(Sp1)cis-acting binding elements in the MKP-1 gene promoter.Amyloid-β(Aβ)-induced Sp1 activation decreased MKP-1 expression.However,upregulation of MKP-1 inhibited the expression of both Aβprecursor protein(APP)andβ-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2(ERK)/MAPK signaling pathway.Furthermore,upregulation of MKP-1 reduced Aβproduction and plaque formation and improved hippocampal long-term potentiation(LTP)and cognitive deficits in APP/PS1 transgenic mice.Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD,whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes.Thus,this study suggests that MKP-1 is a novel molecule for AD treatment.

关键词： Alzheimer Aβ impairment

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项穆书学观念谫论——以《书法雅言》为例

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嘉兴学院学报 2023年第5期35卷 12-17,50页

作者：杨刚逄淑美嘉兴学院设计学院浙江嘉兴314001 嘉兴学院图书馆浙江嘉兴314001

《书法雅言》是明代重要的书学理论著作,作者项穆尊书道、重书统,将书法之工用推到了“同流天地,翼卫教经”的高度。项穆认为,书法是人格的表现、心性的传达,作者器质的不同、性情的差异,导致笔势所运中邪正的分立,正书法就是“正人心”... 详细信息

《书法雅言》是明代重要的书学理论著作,作者项穆尊书道、重书统,将书法之工用推到了“同流天地,翼卫教经”的高度。项穆认为,书法是人格的表现、心性的传达,作者器质的不同、性情的差异,导致笔势所运中邪正的分立,正书法就是“正人心”,“正人心可以闲圣道”,因此,他强调心性与德行。项穆崇尚王羲之书法,重视书法的新变,他贬低苏轼、米芾等人,认为他们与儒家所楬橥的“中和”思想相背离。“中和”是贯穿于《书法雅言》的主线,项穆不仅专设篇章论述,还在其他篇章中时时阐发,认为“中和”之美是书法审美的最高境界。

关键词：嘉兴项穆书法艺术文化

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苦参生物碱的研究

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天然产物研究与开发 1994年第1期6卷 10-13页

作者：赵玉英宠青云刘京渤陈雅研楼之岑北京医科大学药学院植化教研室北京100083 北京医药器械学校中药组

从苦参(Sophora flavescens Ait)根中分离得到9个生物碱,用波谱等方法确定为槐果碱(sophocarpine)、苦参碱(matrine)、异苦参碱(isomatrine)、槐醇(sophoranol)、N-甲基野靛碱(N-methylcytisine)、槐定(sophoridine)、氧化苦参碱(oxymat... 详细信息

关键词：苦参异苦参碱生物碱中草药

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