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Social deficits via dysregulated Rac1-dependent excitability control of prefrontal cortical neurons and increased GABA/glutamate ratios

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收录情况： ◇ SCIE

作者：
Ma Bingke[1,2,3] ; Shan Xingyue[1,2,3] ; Yu Juehua[2,3,4] ; Zhu Tailin[2,3] ; Li Ren[5] ; Lv Hui[2,3] ; Cheng Haidi[1,2,3] ; Zhang Tiantian[1,2,3] ; Wang Lihua[2,3] ; Wei Feiyang[2,3] ; Meng Bo[1] ; Yuan Xiaobing[1] ; Mei Bing[1] ; Zhang Xiao-Yong[5] ; Li Wei-Guang[6] ; Li Fei[2,3] ;
机构： [1]Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), School of Life Sciences, East China Normal University, Shanghai 200062, China [2]Developmental and Behavioral Pediatric Department, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and Ministry of Education - Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China [3]Developmental and Behavioral Pediatric Department, Shanghai Xinhua Children’s Hospital, Shanghai 200092, China [4]Center for Experimental Studies and Research, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China [5]Institute of Science and Technology for Brain-Inspired Intelligence, Ministry of Education - Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education Frontiers Center for Brain Science, Fudan University, Shanghai 200433, China [6]Department of Rehabilitation Medicine, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China
出处：
DOI： 10.1016/j.celrep.2022.111722
ISSN：

摘要：
Identifying symptom-specific convergent mechanisms for neurodevelopmental disorders is a promising strategy in advancing therapies. Here, we show that bidirectional dysregulation of Rac1 activity in the medial prefrontal cortex (mPFC) dictates shared social deficits in mice. Selective upregulation or downregulation of Rac1 activity in glutamatergic or fast-spiking GABAergic neurons results in excessive or inadequate control of excitability combined with a decrease in glutamate or an increase in GABA concentrations and an increase in the GABA/glutamate ratio, which is responsible for social deficits. Notably, the autism model of Shank3B knockout mice exhibits aberrantly enhanced Rac1 activity, reduced glutamate concentrations, and pyramidal neuron excitability in mPFC accompanied with social deficits, which were corrected by either excitatory-neuron-specific downregulation of Rac1 activity or upregulation of neuronal excitability. Thus, this work shows a convergence between genetic autism risk factors, dysregulation of Rac1 signaling, and excitation-inhibition imbalance, enabling mechanism-based stratification of patients with social deficits.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

基金：
We thank Profs. Zhonghua Lu (Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, China) and Dong-Min Yin (East China Normal University, Shanghai, China) for providing Shank3B KO and CaMKIIa-Cre mice, respectively. This study was supported by grants from the National Natural Science Foundation of China (81761128035, 81930095, 82125032, 32071023, 31860306, and 81873893); the Ministry of Science and Technology of the People’s Republic of China (2021ZD0202802); the Science and Technology Commission of Shanghai Municipality (19410713500, 2018SHZDZX01, and 22XD1420700); the Shanghai Municipal Health Commission (GWV-10.1- XK07, 2020CXJQ01, 2018YJRC03, and 2022XD046); the Shanghai Clinical Key Subject Construction Project (shslczdzk02902); and the innovative research team of high-level local universities in Shanghai, the Guangdong Key Project in ‘‘Development of new tools for diagnosis and treatment of autism’’ (2018B030335001).
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外文
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中科院(CAS)分区：
出版当年[2023]版：
大类 | 1 区 生物学
小类 | 2 区 细胞生物学
最新[2023]版：
大类 | 1 区 生物学
小类 | 2 区 细胞生物学
JCR分区：
出版当年[2022]版：
Q1 CELL BIOLOGY
最新[2023]版：
Q1 CELL BIOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2022版] 出版当年五年平均 出版前一年[2021版] 出版后一年[2023版]

第一作者：
第一作者机构： [1]Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), School of Life Sciences, East China Normal University, Shanghai 200062, China [2]Developmental and Behavioral Pediatric Department, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and Ministry of Education - Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China [3]Developmental and Behavioral Pediatric Department, Shanghai Xinhua Children’s Hospital, Shanghai 200092, China
通讯作者：
通讯机构： [2]Developmental and Behavioral Pediatric Department, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and Ministry of Education - Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China [3]Developmental and Behavioral Pediatric Department, Shanghai Xinhua Children’s Hospital, Shanghai 200092, China
推荐引用方式(GB/T 7714)：
Ma Bingke,Shan Xingyue,Yu Juehua,et al.Social deficits via dysregulated Rac1-dependent excitability control of prefrontal cortical neurons and increased GABA/glutamate ratios[J].CELL REPORTS.2022,41(9):doi:10.1016/j.celrep.2022.111722.
APA：
Ma Bingke,Shan Xingyue,Yu Juehua,Zhu Tailin,Li Ren...&Li Fei.(2022).Social deficits via dysregulated Rac1-dependent excitability control of prefrontal cortical neurons and increased GABA/glutamate ratios.CELL REPORTS,41,(9)
MLA：
Ma Bingke,et al."Social deficits via dysregulated Rac1-dependent excitability control of prefrontal cortical neurons and increased GABA/glutamate ratios".CELL REPORTS 41..9(2022)

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