Journal of pharmacological sciencesFeb 10, 2025

Role of specific brain receptors in social behavior problems in mice stressed during youth

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Updated Dec 21, 2025

Abstract

Mice exposed to social defeat stress as juveniles showed elevated levels of GluN2C and GluN2D proteins in the prefrontal cortex.

Dysfunction in the glutamatergic system may relate to stress-related psychiatric disorders.
The role of GluN2C and GluN2D subunits in social behavior impairment is not fully understood.
Using a GluN2C/GluN2D antagonist and ketamine improved social behavior in stressed mice.
The effect of ketamine was partially blocked by a NMDA potentiator.
Increased levels of GluN2C and GluN2D proteins could contribute to social behavior issues after juvenile stress.
Targeting these NMDA receptor subunits may offer new treatment options for adolescents experiencing stress-related disorders.

Simplified

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.

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Declaration of competing interest Dr. Norio Ozaki has received research support, speaker honoraria, or has served as a joint researcher or consultant for Sumitomo Pharma, Otsuka, Viatris, Eisai, Mochida, Kyowa Pharmaceutical Industry, Nihon Medi-Physics, Nippon Chemiphar, Medical Review, Nippon Boehringer Ingelheim, and SUSMED outside the submitted work.

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Role of specific brain receptors in social behavior problems in mice stressed during youth

Abstract

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Competing interests

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