Contribution of GAPDH nuclear translocation in the hippocampus to depression and anxiety-Like behavior in social stressed mice

Abstract

Previous studies indicated that various biological stress has been implicated in enhanced generation of reactive oxygen species (ROS) causing oxidative stress in the brain. Further, robust levels of oxidative stress in the brain has been associated with stress-related neuropsychiatric disorders such as a major depression. But the underlying mechanisms are still unclear. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is well known as a key enzyme of glycolysis, but several lines of evidence suggest that GAPDH is a multifunctional protein which has the strong linkage to oxidative stress. Our study showed that GAPDH nuclear translocation in the hippocampus contributes to depressant-like behavior by using restraint and water immersion stress-models. Then, in this study, we performed the marble burying test as acute social stress models and maternal separation and social isolation (MSSI) stress as chronic social stress models. In the marble burying test, intracerebroventricular injection of male ddY mice with GAPDH-siRNA reduced the number of marbles buried and its stress-induced levels of blood corticosterone. Then, treatment with CGP3466B, an inhibitor of GAPDH nuclear translocation, showed the same effects as that of GAPDH-siRNA. The MSSI stressed mice showed depression and anxiety-like behavior in open field test (OFT), social isolation test (SIT), tail suspension test (TST). And, in this model, GAPDH nuclear translocation in the hippocampus was decreased. Results of marble burying test suggest the correlation of ROS-dependent GAPDH nuclear translocation and acute social stress and could provide its novel therapeutic strategy. And, we will investigate the relationship between GAPDH nuclear translocation and chronic social stress and therapeutic effect by blockade GAPDH nuclear translocation.