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An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons

文献类型：期刊论文

作者Zhang, Jilin2,3; Duan, Jinjin4,5; Li, Wei2,3; Wang, Xian1; Ren, Shimin1; Ye, Luyu3,4; Liu, Fang4; Tian, Xiaoting4; Xie, Yang4; Huang, Yiming2
刊名SCIENCE ADVANCES
出版日期2025-03-05
卷号11期号:10页码:18
ISSN号2375-2548
DOI10.1126/sciadv.adq0444
通讯作者Li, Yang(liyang@simm.ac.cn) ; Zhu, Shujia(shujiazhu@ion.ac.cn) ; Guo, Fei(fguo877@126.com)
英文摘要N-methyl-d-aspartate receptors (NMDARs), key excitatory ion channels, have gained attention as anti-depression targets. NMDARs consist of two GluN1 and two GluN2 subunits (2A-2D), which determine their pharmacological properties. Few compounds selectively targeting GluN2 subunits with antidepressant effects have been identified. Here, we present YY-23, a compound that selectively inhibits GluN2C- or GluN2D-containing NMDARs. Cryo-EM analysis revealed that YY-23 binds to the transmembrane domain of the GluN2D subunit. YY-23 primarily affects GluN2D-containing NMDARs on GABAergic interneurons in the prefrontal cortex, suppressing GABAergic neurotransmission and enhancing excitatory transmission. Behavioral assays demonstrate YY-23's rapid antidepressant effects in both stress-na & iuml;ve and stress-exposed models, which are lost in mice with global or selective knockout of the grin2d gene in parvalbumin-positive interneurons. These findings highlight GluN2D-containing NMDARs on GABAergic interneurons as potential depression treatment targets.
WOS关键词CA2+ MOBILIZATION ASSAYS ; PREFRONTAL CORTEX ; SYNAPTIC PLASTICITY ; DEPENDENT BLOCK ; LARGE-SCALE ; CRYO-EM ; STRESS ; KETAMINE ; DEPRESSION ; SUBUNIT
资助项目General National Natural Science Foundation of China[31771115] ; General National Natural Science Foundation of China[31671049] ; Key Program of National Natural Science Foundation of China[81030065] ; STI2030 Major Projects[2022ZD0212700] ; National Natural Science Foundation of China[32221003] ; CAS Youth Interdisciplinary Team ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB32020000] ; Shanghai Municipal Science and Technology Major Project[2018SHZDZX05] ; Chinese Academy of Sciences[XDA12040214] ; Chinese Academy of Sciences[XDA12040220] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[201909301102] ; Science and Technology Commission of Shanghai Municipality[184319071000] ; Science and Technology Commission of Shanghai Municipality[19140903102] ; Youth Program of National Natural Science Foundation of China[81803828] ; Youth Innovation Promotion Association of Chinese Academy of Science[2019280]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001438146100031
出版者AMER ASSOC ADVANCEMENT SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/316508]  
专题中国科学院上海药物研究所
通讯作者Li, Yang; Zhu, Shujia; Guo, Fei
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210003, Peoples R China
2.Chinese Acad Sci, Inst Neurosci, CAS Ctr Excellence Brain Sci & Intelligence Techno, Shanghai 200031, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China
5.Tongji Univ, Shanghai YangZhi Rehabil Hosp, Shanghai Sunshine Rehabil Ctr, Frontier Sci Ctr Stem Cell Res,Sch Life Sci & Tech, Shanghai 200092, Peoples R China
6.Wenzhou Med Univ, Oujiang Lab, Wenzhou 325000, Zhejiang, Peoples R China
7.Wenzhou Med Univ, Sch Mental Hlth, Wenzhou 325035, Zhejiang, Peoples R China
8.Fudan Univ, Gynecol Hosp, 128 Shenyang Rd, Shanghai 200082, Peoples R China
9.Shanghai Ctr Brain Sci & Brain Inspired Intelligen, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Jilin,Duan, Jinjin,Li, Wei,et al. An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons[J]. SCIENCE ADVANCES,2025,11(10):18.
APA Zhang, Jilin.,Duan, Jinjin.,Li, Wei.,Wang, Xian.,Ren, Shimin.,...&Guo, Fei.(2025).An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons.SCIENCE ADVANCES,11(10),18.
MLA Zhang, Jilin,et al."An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons".SCIENCE ADVANCES 11.10(2025):18.

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来源：上海药物研究所

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