Dysregulated Protein Synthesis in Major Depressive Disorder

Abstract

Abstract Major depressive disorder is a debilitating disorder with a lifetime prevalence of 17% in the adult population. By reverse engineering how antidepressants work at the cellular level, significant progress has been made within the last decade regarding the underlying etiology of depression. Unexpectedly, dysregulation of protein synthesis pathways is at the core of depression. Activation of one or more mRNA translation, initiation, or elongation pathways (including mammalian target of rapamycin [mTOR] kinase, extracellular regulated kinase, and eukaryotic elongation factor 2) is central to symptomatic relief. In preclinical models of stress and/or depression, co-administration of antidepressants and pharmacological inhibitors of these pathways block hallmark characteristics of antidepressant efficacy, including upregulation of key synaptic proteins, increased dendritic and spine complexity, and antidepressant-like behaviors. In this chapter, we review studies demonstrating altered translational pathways in animal models, treated and untreated patients, with a focus on mTOR-regulated protein synthesis.