Abstract
Signal transduction systems mediate cellular responses to changes in the environment, and there is increasing evidence of perturbations in signaling systems in bipolar disorder. Studies in the 1970s revealed that the prototypical mood stabilizer lithium directly modulates the phosphoinositide signal transduction system, which regulates protein kinase C and intracellular calcium, and stimulated research on signaling systems in bipolar disorder. Subsequently, lithium was found to directly inhibit glycogen synthase kinase3. Because glycogen synthase kinase3 regulates a broad spectrum of cellular functions implicated in bipolar disorder, this discovery provided a mechanism to link disparate observations to a cohesive mechanistic basis, including advances in understanding signaling mediated by neurotrophins, implications of altered adult hippocampal neurogenesis linked to the treatment of mood disorders, and altered immune system actions, particularly inflammation, that are linked to mood disorders. Further clarification of perturbed signaling pathways in bipolar disorder may plausibly lead to the development of improved therapies.