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.
Mao
Zhengquan
Z
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
Liu
Liqin
L
Zhang
Rusheng
R
Li
Xiaohua
X
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D047369:Chromatin Immunoprecipitation / Q000379:methods; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects*; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000502:physiology; D009447:Neuroblastoma / Q000473:pathology; D014162:Transfection / Q000379:methods
D014150:Antipsychotic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008094:Lithium