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The Wnt Signaling Pathway in Bipolar Disorder

Laboratory of Molecular Pathophysiology, National Institute of Mental Health Bethesda, Maryland

Husseini K. Manji

Laboratory of Molecular Pathophysiology, National Institute of Mental Health Bethesda, Maryland, manjih{at}intra.nimh.nih.gov

The Wnt signaling pathway is a highly conserved pathway critical for proper embryonic development. However, recent evidence suggests that this pathway and one of its key enzymes, glycogen synthase kinase 3β, may play important roles in regulating synaptic plasticity, cell survival, and circadian rhythms in the mature CNS—all of which have been implicated in the pathophysiology and treatment of bipolar disorder. Furthermore, two structurally highly dissimilar medications used to treat bipolar disorder, lithium and valproic acid, exert effects on components of the Wnt signaling pathway. Together, these data suggest that the Wnt signaling pathway may play an important role in the treatment of bipolar disorder. Here, the authors review the modulation of the Wnt/GSK-3β signaling pathway by mood-stabilizing agents, focusing on two therapeutically relevant aspects: neuroprotection and modulation of circadian rhythms. The future development of selective GSK-3β inhibitors may have considerable utility not only for the treatment of bipolar disorder but also for a variety of classical neurodegenerative disorders.

Key Words: Wnt signaling • Glycogen synthase kinase • Lithium • Valproic acid • Neuroprotection • Circadian rhythms • Bipolar disorder

The Neuroscientist, Vol. 8, No. 5, 497-511 (2002)
DOI: 10.1177/107385802237176


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