title: Lithium reduces FoxO3a transcriptional activity by decreasing its intracellular content.
abstract: 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.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
authors.forename: Zhengquan
authors.initials: Z
authors.lastname: Mao
authors.forename: Liqin
authors.initials: L
authors.lastname: Liu
authors.forename: Rusheng
authors.initials: R
authors.lastname: Zhang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
mesh_terms: 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
chemical_list: D014150:Antipsychotic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008094:Lithium