CA1i pyramidal neurons mediate the role of NMDA receptor subunit GluN3A in depressive behavior and D-serine anti-depression

Depression is a heterogeneous psychiatric disorder characterized by multiple symptom clusters. N-methyl-d-aspartic acid receptors (NMDARs), consisting of various subunit proteins GluN1-3, are known to be critical molecular bases for the occurrence and treatment of depression. However, the involvement of the NMDAR subunit GluN3A in the heterogeneity of depressive symptoms and antidepressant effects remains unclear. Here, we found that chronic social defeat stress (CSDS) induced a range of depression-related behaviors, including decreased social interest, increased helplessness and anxiety-like behavior, and reduced GluN3A mRNA and protein expression in the hippocampal CA1 intermediate (CA1i) region. Additionally, GluN3A knockout (KO) mice exhibited pronounced helplessness behavior. Increasing GluN3A expression in the CA1i in both models specifically reversed the increased helplessness behavior but not social interest and anxiety-like behavior. Furthermore, the lack of CA1i GluN3A expression reduced the activity of CA1i pyramidal neurons in mice during helplessness behavior, a phenomenon also reversed by upregulating CA1i GluN3A expression. Further bidirectional modulation of CA1i pyramidal neuron activity directly mimicked or reversed CSDS-induced helplessness behavior. Finally, injection of D-serine into the CA1i rapidly improved helplessness behavior in CSDS mice while increasing the activity of CA1i pyramidal neurons, whereas knockout of the GluN3A or inhibition of CA1i neuron activity prevented the effect of D-serine. Our study elucidates the critical role of GluN3A subunit in regulating depression-related helplessness behavior and its mechanisms, as well as its role in the rapid antidepressant effect of D-serine, which deepen the understanding of the complex pathophysiology of depression and develop a potential clinical treatment new target.