Glycogen Synthase Kinase-3: A Focal Point for Advancing Pathogenic Inflammation in Depression

Abstract

Increasing evidence indicates that the host immune response has a monumental role in the etiology of major depressive disorder (MDD), motivating the development of the inflammatory hypothesis of depression. Central to the involvement of chronic inflammation in MDD is a wide range of signaling deficits induced by the excessive secretion of pro-inflammatory cytokines and imbalanced T cell differentiation. Such signaling deficits include the glutamatergic, cholinergic, insulin, and neurotrophin systems, which work in concert to initiate and advance the neuropathology. Fundamental to the communication between such systems is the protein kinase glycogen synthase kinase-3 (GSK-3), a multifaceted protein critically linked to the etiology of MDD and an emerging target to treat pathogenic inflammation. Here, a consolidated overview of the widespread multi-system involvement of GSK-3 in contributing to the neuropathology of MDD will be discussed, with the feed-forward mechanistic links between all major neuronal signaling pathways highlighted.

Keywords: MDD; depression; glycogen synthase kinase 3; inflammation; oxidative stress.

Figure 1

Multifaceted involvement of GSK-3 in promoting MDD neuropathology. Several bidirectional signaling pathways work cooperatively to elevate GSK-3 activity in MDD. Such processes, initiating from the DAMP-mediated activation of the TLR4, include the heightened production of inflammatory cytokines from NF-κB and STAT3 with subsequent suppression of anti-inflammatory cytokines and antioxidant factors from Nrf2 and CREB. Imbalanced cytokine production results in modified cellular differentiation of T helper cells into pro-inflammatory Th1 and Th17 cell variants, with synchronous reductions to the proliferation of Th2 cells and Tregs. Inflammatory cytokines TNF-α, IL-6, IL-1β, and IFN-γ stimulate IDO to metabolize TRP into KYN which is further metabolized into QUIN and KYNA. Downstream effects of IDO activation include reduced 5-HT and α7nAChR signaling, and enhanced NMDA and IFN-γ signaling, collectively inhibiting PI3K and Akt, and disinhibiting GSK-3, which subsequently inhibits the action of insulin. Positive regulation (red arrows) and negative regulation (blue arrows) of each pathway and/or process are shown. Changes in the overall activity of these pathways compared to normal conditions are represented by the solid arrows (increased activity) and dotted arrows (decreased activity). α7nAChR, α7 nicotinic acetylcholine receptor; BDNF, brain-derived neurotrophic factor; CREB, cAMP-response element binding protein; DAMP, danger-associated molecular patterns; GSK-3, glycogen synthase kinase 3; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon gamma; IL-1β, interleukin 1 beta; IL-4, interleukin 4; IL-6, interleukin 6; IL-10, interleukin 10; IL-12, interleukin 12; IL-17, interleukin 17; KYN, kynurenine; KYNA, kynurenic acid; MAO-A/B, monoamine-degrading enzyme A/B; NF-κB, nuclear factor kappa B; NMDA, N-methyl-D-aspartic acid; NRF2, nuclear factor-erythroid factor 2-related factor 2; PI3K, phosphoinositide 3-kinase; QUIN, quinolinic acid; STAT3, signal transducer and activation of transcription 3; Th1, T helper cell type 1; Th17, T helper cell type 17; Th2, T helper cell type 2; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor alpha; TNF- β, tumor necrosis factor beta; Treg, regulatory T cell; TRP, tryptophan; 5-HT, serotonin. Figure created with BioRender.com.