RAGE signaling pathway is involved in CUS-induced depression-like behaviors by regulating the expression of NR2A and NR2B in rat hippocampus DG.

NMDA receptors play pivotal roles in the neurobiology of chronic stress-induced mood disorders. But the mechanism for chronic stress to disturb the expression of NMDA receptor subunits is still unclear. Recent researches indicated the involvement RAGE signaling pathway in regulation of glutamate system functions. In this study, we hypothesized RAGE signaling pathway mediated chronic stress-induced alteration in the expression of NMDA receptor subunits, leading to depressive-like behaviors. CUS decreased the expression of RAGE, NR2A, and NR2B, inhibited the phosphorylation of transcript factor ERK and CREB in rat hippocampus DG. RAGE knockdown in hippocampus DG by RAGE shRNA lentiviral particles induced depressive-like behaviors, reduced the mRNA and protein expression of NR2A and NR2B, and inhibited the phosphorylation of ERK and CREB. RAGE over-expression in hippocampus DG by RAGE adenovirus particles reversed the effects of CUS on depressive-like behaviors, ERK and CREB phosphorylation, and NR2A and NR2B expression. Our findings suggests that RAGE signaling pathway at least partially participates in the regulation of NR2A and NR2B expression, which mediates the effects of chronic stress on the depressive-like behaviors. These data provide evidence for RAGE signaling as a possible new pathway through which chronic stress results in the maladaptation of NMDA receptors.