Involvement of N-methyl-D-aspartate receptor GluN2C/GluN2D subunits in social behavior impairments in mice exposed to social defeat stress as juveniles.
Journal of pharmacological sciences – March 01, 2025
Source: PubMed
Summary
Early-life social stress can trigger lasting behavioral changes. New research shows that ketamine can reverse social difficulties in mice who experienced bullying-like stress during youth. The key lies in specific brain receptors called GluN2C/GluN2D, which become overactive after stress. Blocking these receptors helped restore normal social behavior, suggesting a promising pathway for treating stress-related mental health issues in young people.
Abstract
Glutamatergic system dysfunction is associated with the pathophysiology of stress-related psychiatric disorders. However, the role of N-methyl-D-aspartate (NMDA) receptor GluN2C and GluN2D subunits in the pathophysiology of adverse juvenile experiences remain unclear. This study aimed to investigate the involvement of GluN2C and GluN2D subunits in social behavior impairments in mice exposed to social defeat stress as juveniles. Acute administration of PPDA, a GluN2C/GluN2D antagonist, and ketamine, a non-competitive NMDA receptor antagonist, attenuated social behavior impairments in stressed mice. This attenuating effect of ketamine was partially inhibited by the administration of CIQ, a GluN2C/GluN2D-containing NMDA potentiator. The prefrontal cortex of stressed mice exhibited significantly elevated levels of GluN2C and GluN2D proteins compared to control mice. These findings suggest that activation of GluN2C- and/or GluN2D-containing NMDA receptors contributes to the development of social behavioral impairments induced by juvenile social defeat stress. Moreover, these subunits may play a role in the therapeutic effects of ketamine. Targeting GluN2C/GluN2D subunits of NMDA receptors may be novel therapeutic strategies for stress-related psychiatric disorders in adolescents with adverse juvenile experiences.