Excessive activation of the loop between the NR2B subunit of the N-methyl-d-aspartate receptor and glycogen synthase kinase-3β in the hippocampi of patients with major depressive disorder

Objective: We showed previously that glycogen synthase kinase-3 beta (GSK-3 beta) levels are significantly elevated in the hippocampi of patients with major depressive disorder (MDD). However, the exact cause of this elevation and its function are unknown. Recent animal studies have suggested a mechanism involving the N-methyl-d-aspartate (NMDA) NR2B-GSK-3 beta loop. Methods: To investigate the existence of an NR2B-GSK-3 beta loop in the hippocampi of patients with MDD, we examined the expression of NR2B. We also attempted to identify markers that correlate with NR2B levels in the hippocampus, using the Stanley Neuropathology Consortium Integrative Database (SNCID). The SNCID is a web-based tool used to integrate Stanley Medical Research Institute (SMRI) data sets. Results: We found that hippocampal levels of NR2B and DLGAP1 mRNA were higher in the MDD group (n = 8) than in unaffected controls (n = 12) (p < 0.05). NR2B expression levels were correlated with the expression levels of NR2A, NR1, DLGAP1, GSK-3 beta and nitric oxide synthase 1, as well as with the number of calretinin-immunoreactive neurons in the hippocampus in all subjects in the SNC (n = 42, p < 0.001). Conclusion: The results of our study show the possible involvement of excessive activation of the NR2B-GSK-3 beta loop in the overexpression of GSK-3 beta in the hippocampi of patients with MDD.