NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism

•N-methyl-D-aspartate receptor (NMDAR) targeting drugs may be efficacious for treating mood disorders.•NMDAR, AMPAR and glutamate receptor interacting molecules, including PSD-95, are implicated in antidepressant-related behaviors.•Global GluA1 or PSD-95 knockout, or systemic GluN2B antagonist (Ro 25-6981) in C57BL/6J, reduced FST immobility.•GluN2B antagonism reduced FST immobility in GluA1 or interneuronal GluN1 knockouts, but not GluN2A or PSD-95 knockouts.•GluN2B antagonist microinfusion into medial prefrontal cortex, not basolateral amygdala, reduced FST immobility in C57BL/6J.

Drugs targeting the glutamate N-methyl-d-aspartate receptor (NMDAR) may be efficacious for treating mood disorders, as exemplified by the rapid antidepressant effects produced by single administration of the NMDAR antagonist ketamine. Though the precise mechanisms underlying the antidepressant-related effects of NMDAR antagonism remain unclear, recent studies implicate specific NMDAR subunits, including GluN2A and GluN2B, as well as the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunit glutamate receptor interacting molecule, PSD-95. Here, integrating mutant and pharmacological in mice, we investigated the contribution of these subunits and molecules to antidepressant-related behaviors and the antidepressant-related effects of the GluN2B blocker, Ro 25-6981. We found that global deletion of GluA1 or PSD-95 reduced forced swim test (FST) immobility, mimicking the antidepressant-related effect produced by systemically administered Ro 25-6981 in C57BL/6J mice. Moreover, the FST antidepressant-like effects of systemic Ro 25-6981 were intact in mutants with global GluA1 deletion or GluN1 deletion in forebrain interneurons, but were absent in mutants constitutively lacking GluN2A or PSD-95. Next, we found that microinfusing Ro 25-6981 into the medial prefrontal cortex (mPFC), but not basolateral amygdala, of C57BL/6J mice was sufficient to produce an antidepressant-like effect. Together, these findings extend and refine current understanding of the mechanisms mediating antidepressant-like effects produced by NMDAR-GluN2B antagonists, and may inform the development of a novel class of medications for treating depression that target the GluN2B subtype of NMDAR.