INS and major depressive disorder: Specifically, with an initial insult of stress-meditated activation of the TLR4, it is possible that GSK-3 actions, in concert with inflammatory cytokines, such as IFN-γ and TNF-α, promote the development of MDD via the reduction in 5-HT and insulin signaling, upregulated NMDA transmission, and aberrant neuronal oscillatory functionality.