Non-classical NMDAR subunit GluN3A in a specialized hippocampal region regulates stress-coping strategies in male mice.

The hippocampus exhibits marked structural, functional, and molecular heterogeneity. GluN3A, a non-classical N-methyl-D-aspartate receptor subunit enriched in hippocampal CA1, has a poorly understood role in stress-related behavior. Here, using chronic social defeat stress (CSDS), GluN3A knockout mice, and behavioral, molecular, genetic, pharmacological, and circuit analyses, we investigated the role of hippocampal GluN3A in stress coping. CSDS selectively reduced GluN3A expression in intermediate CA1 (CA1i), and both stress-induced and genetic GluN3A loss promoted passive coping, whereas CA1i-specific GluN3A overexpression reversed this phenotype. c-Fos staining, fiber photometry, and chemogenetic manipulations showed that GluN3A is required for CA1i pyramidal neuron activation during coping. In addition, local D-serine administration rapidly shifted coping from passive to active in a GluN3A-dependent manner. Circuit tracing showed that CA1i neurons project broadly, and GluN3A overexpression selectively enhanced downstream activity in CA3 and infralimbic cortex. Together, these findings identify GluN3A in CA1i as a key regulator of stress-coping behavior.