An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons
<i>N</i>-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 <i>grin2d</i> gene in parvalbumin-positive interneurons. These findings highlight GluN2D-containing NMDARs on GABAergic interneurons as potential depression treatment targets.
Authors
- Jilin Zhang (ORCID: https://orcid.org/0000-0002-7847-6899)
- Shengxiang Ren (ORCID: https://orcid.org/0000-0001-8767-9850)
- Shujia Zhu (ORCID: https://orcid.org/0000-0001-8358-2859)
- Luyu Ye (ORCID: https://orcid.org/0000-0001-8529-4148)
- Xiaoting Tian (ORCID: https://orcid.org/0000-0003-0379-9770)
- Xiang Cai
- Nan Song
- Jinjin Duan
- Hu Zhou (ORCID: https://orcid.org/0000-0001-7006-4737)
- Chenggang Huang (ORCID: https://orcid.org/0000-0001-9209-7484)
- Tianyu Li (ORCID: https://orcid.org/0000-0001-9197-3315)
- Zhiqiang Liu (ORCID: https://orcid.org/0000-0002-3489-9101)
- Yang Li (ORCID: https://orcid.org/0000-0001-7182-6756)
- Fang Liu (ORCID: https://orcid.org/0000-0002-2073-1682)
- Fei Guo (ORCID: https://orcid.org/0000-0003-3870-337X)
- Yiming Huang (ORCID: https://orcid.org/0009-0009-7531-039X)
- Yidi Sun (ORCID: https://orcid.org/0000-0002-4191-2917)
- Wei Li (ORCID: https://orcid.org/0000-0003-4464-2446)
- Yang Xie
- Xian Wang (ORCID: https://orcid.org/0000-0002-4017-8036)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- Wenzhou Medical University (CN)
- Center for Excellence in Brain Science and Intelligence Technology (CN)
- Shanghai Institute of Materia Medica (CN)
- Shanghai Sunshine Rehabilitation Center (CN)
- Obstetrics and Gynecology Hospital of Fudan University (CN)
- Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1126/sciadv.adq0444
- Citations
- 5
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 4.55