2. Academic Validation
  3. An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons

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

  • Sci Adv. 2025 Mar 7;11(10):eadq0444. doi: 10.1126/sciadv.adq0444.
Jilin Zhang 1 2,  Jinjin Duan 3 4,  Wei Li 1 2,  Xian Wang 5,  Shimin Ren 5,  Luyu Ye 2 3,  Fang Liu 3,  Xiaoting Tian 3,  Yang Xie 3,  Yiming Huang 1,  Yidi Sun 1,  Nan Song 1,  Tianyu Li 2 3,  Xiang Cai 6 7,  Zhiqiang Liu 8,  Hu Zhou 8,  Chenggang Huang 3,  Yang Li 3 5,  Shujia Zhu 1 2 9,  Fei Guo 3 8
Affiliations

Affiliations

  • 1 Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
  • 2 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 3 Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210003, China.
  • 6 Oujiang Laboratory, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 7 School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 8 Gynecology Hospital of Fudan University, No. 128, Shenyang Rd, Yangpu District, Shanghai 200082, China.
  • 9 Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China.
PMID: 40043126 DOI: 10.1126/sciadv.adq0444
Abstract

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-naïve 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.

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