Lithium Reduces FoxO3a Transcriptional Activity by Decreasing Its Intracellular Content

Background Forkhead box, class O (FoxO) transcription factors play important roles in cell fate, differentiation, survival, and stress regulation. A subtype of mammalian FoxO transcription factors, FoxO3a, is widely distributed in the brain, and its activity is regulated by neurotrophins, such as brain-derived neurotrophic factor (BDNF), resulting in transcriptional inactivation of FoxO3a. Searching for therapeutic targets downstream of BDNF signaling will facilitate the development of new treatment approaches for mood disorders. Methods Transcriptional activity, target gene expression, and protein levels of FoxO3a were measured in cultured cells and mouse brain after lithium treatment. Results Lithium significantly reduced FoxO3a transcriptional activity and gene expression. The effect of lithium may be the result of a significant reduction of the FoxO3a protein levels in both the cytosol and nucleus that was mediated by an Akt-independent action. More importantly, this effect of lithium was observed in cells and mouse brain after therapeutically relevant lithium treatments. Conclusions Lithium, an established treatment for mood disorders, has a prominent effect on FoxO3a transcriptional activity and the effect is likely therapeutically relevant. These results warrant further study to identify if FoxO3a is a transcriptional target in the neuropathology and treatment of mood disorders.