Is glycogen synthase kinase-3 a central modulator in mood regulation?

Abstract

Little is known regarding the mechanisms underlying the complex etiology of mood disorders, represented mainly by major depressive disorder and bipolar disorder. The 1996 discovery that lithium inhibits glycogen synthase kinase-3 (GSK3) raised the possibility that impaired inhibition of GSK3 is associated with mood disorders. This is now supported by evidence from animal biochemical, pharmacological, molecular, and behavioral studies and from human post-mortem brain, peripheral tissue, and genetic studies that are reviewed here. Mood disorders may result in part from impairments in mechanisms controlling the activity of GSK3 or GSK3-regulated functions, and disruptions of these regulating systems at different signaling sites may contribute to the heterogeneity of mood disorders. This substantial evidence supports the conclusion that bolstering the inhibitory control of GSK3 is an important component of the therapeutic actions of drugs used to treat mood disorders and that GSK3 is a valid target for developing new therapeutic interventions.

Figures

Figure 1

Schematic illustration of signaling pathways regulating GSK3 and functions of GSK3 related to mood regulation. GSK3 is regulated by BDNF, serotonin, and dopamine through the Akt signaling pathway, by the NMDA receptor through protein phosphatases, and by Wnt signaling in the Axin-β-catenin protein complex. Active GSK3 phosphorylates substrate proteins and affects gene expression, synaptic plasticity, and neurogenesis, which in turn regulate mood-related behaviors. Abbreviations: α,β,γ, G-protein subunits; β-arr, β-arrestin; BD, bipolar disorder; BDNF, brain-derived neurotrophic factor; DA, dopamine; D2, type 2 dopamine receptor; DISC1, disrupted in schizophrenia 1; GSK3, glycogen synthase kinase-3; 5HT, serotonin; 5HT1A, 1B, 2A, serotonin receptor subtypes; LTD, long term depression; NMDA, N-methyl--aspartic acid; P, phosphorylated; PDK1, phosphoinositide-dependent kinase-1; PI3K, phosphatidylinositol-3-kinase; PP1, PP2A, PP2B, protein phosphatase 1, 2A, and 2B; TF, transcription factors; TrKB, type B tropomyosin-receptor-kinase; YMRS, Young Mania Rating Scale.