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
  • 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.

Products