Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Abstract

The neurobiology of bipolar disorder, a chronic and systemic ailment is not completely understood. The bipolar phenotype manifests in myriad ways, and psychopharmacological agents like lithium have long term beneficial effects. The enzyme glycogen synthase kinase 3 (GSK3) has come into focus, as lithium and several other mood stabilizing medications inhibit its activity. This kinase and its key upstream modulator, Wnt are dysregulated in mood disorders and there is a growing impetus to delineate the chief substrates involved in the development of these illnesses. In May 2016, a comprehensive literature search was undertaken which revealed that there is over activity of GSK3 in bipolar disorder with deleterious downstream effects like proinflammatory status, increased oxidative stress, and circadian dysregulation leading to declining neurotrophic support and enhanced apoptosis of neural elements. By developing specific GSK3 inhibitors the progressive worsening in bipolar disorder can be forestalled with improved prospects for the sufferers.

Keywords: Bipolar disorder; Canonical Wnt pathway; Glycogen synthase kinase 3; Protein kinase B; Wnt; β-catenin.

Fig. 1

Inhibitory regulation of glycogen synthase kinase 3 (GSK3). GSK3 is a multi-functioning enzyme that acts as a controlling switch for several crucial intracellular signaling cascades. Insulin/growth factors/neurotrophins, acting through protein kinase B (Akt) cause serine phosphorylation of an N-terminal residue leading to the formation of pseudo-substrate and loss of kinase function of GSK3. Dorsophila wingless protein (Wnt) signaling, on the contrary disrupts the Axin complex in which the constitutively active GSK3 is held in a scaffold. The mood stabilizer, lithium inhibits both of these GSK3 pools; C-terminal tyrosine phosphorylation is most probably an intramolecular event that is considered essential for GSK3 regulation.

Fig. 2

The canonical Dorsophila wingless protein (Wnt) pathway. Wnt ligands play an essential role in neuronal proliferation, migration and fate. Wnt proteins bind to their transmembrane receptor, frizzled (Fz), recruiting the phospho-protein dishevelled (Dvl) and activating the co-receptors LRP5/6. The later cause disruption of a complex in which the intrinsically active glycogen synthase kinase 3 (GSK3) phosphorylates the transcriptional co-activator, β-catenin. The unphosphorylated β-catenin builds-ups in the cytoplasm, which facilitates its entry into the nucleus. In the nucleus, β-catenin interacts with lymphocyte enhancer factor/T-cell factor family of transcription factors, causing expression of the Wnt responsive genes.

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.

Fig. 4

Pharmacotherapy of bipolar disorder. Bipolar disorder is a difficult to treat condition, as affective symptoms may persist during the inter-episode period. Less than one third of patients show responsiveness to the classical mood stabilizer, lithium (Li). New generation anticonvulsants are being employed with increasing frequency with favorable efficacy and safety profile. Atypical antipsychotics control core affective symptoms and are also useful in comorbid anxiety and substance use disorders. Antidepressants employed as monotherapy are liable to induce mixed states, subthreshold symptoms and rapid cycling.