The Concept of Dysregulated Signal Transduction and Gene Expression in the Pathophysiology of Mood Disorders

Novel mechanistic concepts of the neurobiology of depression and bipolar disorder are evolving based on recent pre-clinical and clinical studies. Ongoing research could lead not only to a breakthrough in identifying the causative factors associated with mood disorders but also to the development of novel therapeutic interventions. One such recent breakthrough concerns the observed abnormalities in the two major signal transduction mechanisms most implicated in mood disorders: adenylyl-cyclase cyclic adenosine monophosphate (AC cAMP) and phosphoinositide (PI) hydrolysis. Among them are abnormalities in GTP binding proteins, phosphorylating enzymes, and substrate molecules observed in peripheral tissues and postmortem brain. More recently, cell survival pathways, such as the extracellular signal-regulated kinase and the Wnt pathways, which also cross-talk with AC-cAMP and PI signaling, have been investigated to elucidate their roles in the pathophysiology of mood disorders. Important consequences of the activation of these diverse signaling pathways are a modulation in the activation of transcription factors and, ultimately, in the regulation of gene expression. Particular attention is being paid to the roles of the transcription factor cAMP-response element binding protein and its target gene, brain-derived neurotrophic factor. Moreover, newer technologies, including complementary DNA microarray analysis, are revealing novel genes relevant to mood disorders. This critical overview presents our own and other groups' findings on various aspects of these signal transduction mechanisms, and on the regulation of gene expression, relevant to the pathophysiology of mood disorders.