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Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons

文献类型：期刊论文

作者Zhang, Yong-mei8,9,10; Zong, Hai-chao8,10; Qi, Ying-bei8,9,10; Chang, Liu-liu8,10; Gao, Ya-nan7,10; Zhou, Ting8,10; Yin, Tao8,10; Liu, Meng8,10; Pan, Kai-jun7,10; Chen, Wen-gang7,10
刊名MOLECULAR PSYCHIATRY
出版日期2023-10-05
页码11
ISSN号1359-4184
DOI10.1038/s41380-023-02283
通讯作者Zang, Yi(yzang@simm.ac.cn) ; Li, Yang(liyang@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn)
英文摘要Diabetic patients receiving the antidiabetic drug metformin have been observed to exhibit a lower prevalence of anxiety disorders, yet the precise mechanism behind this phenomenon is unclear. In our study, we found that anxiety induces a region-specific reduction in AMPK activity in the medial prefrontal cortex (mPFC). Concurrently, transgenic mice with brain-specific AMPK knockout displayed abnormal anxiety-like behaviors. Treatment with metformin or the overexpression of AMPK restored normal AMPK activity in the mPFC and mitigated social stress-induced anxiety-like behaviors. Furthermore, the specific genetic deletion of AMPK in the mPFC not only instigated anxiety in mice but also nullified the anxiolytic effects of metformin. Brain slice recordings revealed that GABAergic excitation and the resulting inhibitory inputs to mPFC pyramidal neurons were selectively diminished in stressed mice. This reduction led to an excitation-inhibition imbalance, which was effectively reversed by metformin treatment or AMPK overexpression. Moreover, the genetic deletion of AMPK in the mPFC resulted in a similar defect in GABAergic inhibitory transmission and a consequent hypo-inhibition of mPFC pyramidal neurons. We also generated a mouse model with AMPK knockout specific to GABAergic neurons. The anxiety-like behaviors in this transgenic mouse demonstrated the unique role of AMPK in the GABAergic system in relation to anxiety. Therefore, our findings suggest that the activation of AMPK in mPFC inhibitory neurons underlies the anxiolytic effects of metformin, highlighting the potential of this primary antidiabetic drug as a therapeutic option for treating anxiety disorders.
WOS关键词PROTEIN-KINASE ; PREFRONTAL CORTEX ; ANXIETY DISORDERS ; VISUAL-CORTEX ; MECHANISMS ; DEPRESSION ; BEHAVIORS ; IMPROVES ; METABOLISM ; GLUCOSE
资助项目We thank Dr. Mu-ming Poo for conceptional discussions and manuscript editing. We thank Dr. Zhen Zhang and Dr. Shan-shan Su for helpful discussions and Dr. Hailan Hu's laboratory for technical assistance. We thank Dr. Xiang Yu for offering VgatVgatVgatVgatVgatVgat
WOS研究方向Biochemistry & Molecular Biology ; Neurosciences & Neurology ; Psychiatry
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:001076207800001
源URL[http://119.78.100.183/handle/2S10ELR8/307294]  
专题新药研究国家重点实验室
通讯作者Zang, Yi; Li, Yang; Li, Jia
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Drug Discovery Shandong Lab, Yantai 264117, Shandong, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Guangzhou 528400, Peoples R China
3.Fudan Univ, Huashan Hosp, Natl Clin Res Ctr Aging & Med, Shanghai 200040, Peoples R China
4.Lin Gang Lab, Shanghai 200031, Peoples R China
5.Shanghai Jiao Tong Univ, Shanghai Mental Hlth Ctr, Sch Med, Shanghai Key Lab Psychot Disorders, Shanghai 200025, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Neuropharmacol, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
7.China Pharmaceut Univ, Inst Pharmaceut Sci, Nanjing 210009, Jiangsu, Peoples R China
8.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
9.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Zhejiang, Peoples R China
10.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Yong-mei,Zong, Hai-chao,Qi, Ying-bei,et al. Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons[J]. MOLECULAR PSYCHIATRY,2023:11.
APA Zhang, Yong-mei.,Zong, Hai-chao.,Qi, Ying-bei.,Chang, Liu-liu.,Gao, Ya-nan.,...&Li, Jia.(2023).Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons.MOLECULAR PSYCHIATRY,11.
MLA Zhang, Yong-mei,et al."Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons".MOLECULAR PSYCHIATRY (2023):11.

入库方式： OAI收割

来源：上海药物研究所

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