Neurobiology of depression: The role of glycogen synthase kinase 3

Major depression disorder (MDD) is a common mental disorder; more than 264 million people suffer from MDD, causing a substantial social and economic burden in the United States and worldwide. Despite some clinical success with current antidepressant medications, a significant portion of patients develop resistance to or are insensitive to current therapeutics, highlighting the need for new therapeutics against MDD. Because of the complexity of the disorder, advances in prevention and treatment of depression require an in-depth understanding of the molecular mechanisms underlying its pathophysiology. Among the many molecular targets implicated in MDD is glycogen synthase kinase 3 (GSK3), an evolutionarily conserved enzyme with enriched expression in the brain. This chapter provides a general overview of the basic mechanisms of regulation of GSK3 and evidence for new targets in experimental models of depression-like behavior, with the intent of providing new potential molecular targets for the pharmacological treatment of MDD.