A novel antidepressant actingviaallosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons

加巴能 兴奋性突触后电位 神经科学 神经传递 变构调节 化学 NMDA受体 谷氨酸受体 变构调节剂 前额叶皮质 谷氨酸的 受体 生物 生物化学 认知
作者
Jilin Zhang,Jinjin Duan,Luyu Ye,Wei Li,Haitao Zhou,Fang Liu,Xiaoting Tian,Yang Xie,Yiming Huang,Yidi Sun,Hu Zhou,Chenggang Huang,Yang Li,Shujia Zhu,Fei Guo
标识
DOI:10.1101/2022.11.06.514872
摘要

Abstract N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated calcium-permeable excitatory channels. They have attracted great interest as potential targets for the treatment of depression in recent years. NMDARs typically assemble as heterotetramers composed of two GluN1 and two alternative GluN2 (2A-2D) subunits, the latter of which endow various subtypes with diverse gating and pharmacological properties. To date, limited molecules with GluN2 specificity have been identified to show antidepressant effects. Here, we identify a compound termed YY-23 extracted from Rhizoma Anemarrhenae allosterically inhibited the channel activities of GluN2C- or GluN2D-incorporated NMDARs, an effect that was presumably influenced by the S2 segment in the ligand-binding domain of the GluN2 subunit. We found that prefrontal GluN2D-containing NMDARs were predominantly expressed at GABAergic interneurons rather than pyramidal neurons. Furthermore, we revealed that YY-23 suppressed the activity of GluN2D-containing NMDARs and GABAergic neurotransmission in the medial prefrontal cortex (mPFC). As a consequence, this GABAergic disinhibition facilitated the excitatory transmission. Behavioural experiments showed that YY-23 acted as a rapid antidepressant in both stress-naïve and stressed animal models, which was abolished in Grin2d-knockout mice. Together, our findings suggest that GluN2D-incorporated NMDARs on GABAergic interneurons might be promising therapeutic targets for the treatment of depression.
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