An antidepressant mechanism involving inhibition of specific NMDA receptors in brain cells that control inhibition

YY-23 selectively inhibits GluN2C- or GluN2D-containing NMDA receptors.

• Cryo-EM analysis shows YY-23 binds to the transmembrane domain of the GluN2D subunit.
• YY-23 suppresses GABAergic neurotransmission while enhancing excitatory transmission in the prefrontal cortex.
• Behavioral assays indicate rapid antidepressant effects of YY-23 in both stress-naïve and stress-exposed mouse models.
• The antidepressant effects of YY-23 are lost in mice lacking the gene in specific interneurons.

Simplified