Targeting Signal Transduction Pathways in the Treatment of Mood Disorders: Recent Insights into the Relevance of the Wnt Pathway

Todd   D.   Gould; Eliot   R.   Dow; Kelley   C.   O'Donnell; Guang      Chen; Husseini   K.   Manji

Abstract

Regulation of complex signaling pathways plays a critical role in higher-order brain functions including the regulation of mood, cognition, appetite, sexual arousal, sleep patterns, and weight, all of which are altered in mood disorders, suggesting the involvement of signaling pathways in mood disorder pathogenesis and pathophysiology. Most existing medications used to treat mood disorders take many weeks to exert their full clinical effects, a fact which implicates changes in gene and protein expression, as well as neuroplasticity, in their mechanism of action. Modulation of signaling pathways has many downstream effects on gene expression and protein function, causing changes in synaptic function, plasticity, and response to various inputs such as neurohormones. The Wnt signaling pathway has recently been linked to the therapeutically relevant actions of available treatments of mood disorders. We provide a brief introduction to signaling cascades and their potential roles in mood disorder pathophysiology and treatment. Subsequently, we describe the Wnt signaling pathway, and glycogen synthase kinase-3 (GSK-3) and beta-catenin specifically, discussing studies that have implicated these proteins as relevant to the pathophysiology and treatment of mood disorders. Future directions, aimed at understanding mood disorders and developing more efficacious treatments, are also discussed.

Keywords: Bipolar disorder, manic-depressive illness, depression, mania, lithium, valproate, antidepressant, glycogen synthase kinase-3, treatment, animal models