Fig. 3.

Up- and down-stream modulators of glycogen synthase kinase (GSK) 3β that regulate mood. GSK3 is hyperactivated in major mood disorders, downstream of monoaminergic signaling, DISC1, neuregulin and brain derived neurotrophic factor (BDNF). These diverse mediators converge through the PI3K/Akt cascade and lead to the inhibition of GSK3. In addition, wingless Drosophila proteins (Wnt) molecules acting via their transmembrane receptors and cytosolic effectors also inactivate GSK3. There is cross-talk between these two pathways by means of mammalian target of rapamycin (mTOR) and heat inducible factor (HIF) 1α; mTOR is activated by Akt which promotes HIF-1α translation, increasing expression of Wnt target genes. The downstream modulators of GSK3β have crucial mood regulating effects through augmented mechanisms which include increased neurotrophic support, dendritic growth and arborization and enhanced synaptic plasticity. This process of neuroprotection is promoted by psychotropic drugs by virtue of their inhibitory action on GSK3 activity.

Akt, protein kinase B; DISC1, disrupted in schizophrenia 1; Dvl, dishevelled; Fz, frizzled; Li, lithium; LRP, low density lipoprotein receptor related protein; PI3K, phosphoinositide 3-kinase.