Forkhead Box, Class O Transcription Factors in Brain: Regulation and Behavioral Manifestation

Abigail Polter, Sufen Yang, Anna A. Zmijewska, Thomas van Groen, Ji Hye Paik, Ronald A. DePinho, Stanford L. Peng, Richard S Jope, Xiaohua Li

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Background: The mammalian forkhead box, class O (FoxO) transcription factors function to regulate diverse physiological processes. Emerging evidence that both brain-derived neurotrophic factor (BDNF) and lithium suppress FoxO activity suggests a potential role of FoxOs in regulating mood-relevant behavior. Here, we investigated whether brain FoxO1 and FoxO3a can be regulated by serotonin and antidepressant treatment and whether their genetic deletion affects behaviors. Methods: C57BL/6 mice were treated with d-fenfluramine to increase brain serotonergic activity or with the antidepressant imipramine. The functional status of brain FoxO1 and FoxO3a was audited by immunoblot analysis for phosphorylation and subcellular localization. The behavioral manifestations in FoxO1- and FoxO3a-deficient mice were assessed via the Elevated Plus Maze Test, Forced Swim Test, Tail Suspension Test, and Open Field Test. Results: Increasing serotonergic activity by d-fenfluramine strongly increased phosphorylation of FoxO1 and FoxO3a in several brain regions and reduced nuclear FoxO1 and FoxO3a. The effect of d-fenfluramine was mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Chronic, but not acute, treatment with the antidepressant imipramine also increased the phosphorylation of brain FoxO1 and FoxO3a. When FoxO1 was selectively deleted from brain, mice displayed reduced anxiety. In contrast, FoxO3a-deficient mice presented with a significant antidepressant-like behavior. Conclusions: FoxOs may be a transcriptional target for anxiety and mood disorder treatment. Despite their physical and functional relatedness, FoxO1 and FoxO3a influence distinct behavioral processes linked to anxiety and depression. Findings in this study reveal important new roles of FoxOs in brain and provide a molecular framework for further investigation of how FoxOs may govern mood and anxiety disorders.

Original languageEnglish
Pages (from-to)150-159
Number of pages10
JournalBiological Psychiatry
Volume65
Issue number2
DOIs
StatePublished - Jan 15 2009
Externally publishedYes

Fingerprint

Transcription Factors
Fenfluramine
Brain
Antidepressive Agents
Imipramine
Phosphorylation
Anxiety Disorders
Mood Disorders
Anxiety
Phosphatidylinositol 3-Kinase
Physiological Phenomena
Hindlimb Suspension
Brain-Derived Neurotrophic Factor
Inbred C57BL Mouse
Lithium
Serotonin
Therapeutics
Depression

Keywords

  • Akt
  • antidepressant
  • anxiety
  • depression
  • FoxOs
  • serotonin

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Polter, A., Yang, S., Zmijewska, A. A., van Groen, T., Paik, J. H., DePinho, R. A., ... Li, X. (2009). Forkhead Box, Class O Transcription Factors in Brain: Regulation and Behavioral Manifestation. Biological Psychiatry, 65(2), 150-159. https://doi.org/10.1016/j.biopsych.2008.08.005

Forkhead Box, Class O Transcription Factors in Brain : Regulation and Behavioral Manifestation. / Polter, Abigail; Yang, Sufen; Zmijewska, Anna A.; van Groen, Thomas; Paik, Ji Hye; DePinho, Ronald A.; Peng, Stanford L.; Jope, Richard S; Li, Xiaohua.

In: Biological Psychiatry, Vol. 65, No. 2, 15.01.2009, p. 150-159.

Research output: Contribution to journalArticle

Polter, A, Yang, S, Zmijewska, AA, van Groen, T, Paik, JH, DePinho, RA, Peng, SL, Jope, RS & Li, X 2009, 'Forkhead Box, Class O Transcription Factors in Brain: Regulation and Behavioral Manifestation', Biological Psychiatry, vol. 65, no. 2, pp. 150-159. https://doi.org/10.1016/j.biopsych.2008.08.005
Polter, Abigail ; Yang, Sufen ; Zmijewska, Anna A. ; van Groen, Thomas ; Paik, Ji Hye ; DePinho, Ronald A. ; Peng, Stanford L. ; Jope, Richard S ; Li, Xiaohua. / Forkhead Box, Class O Transcription Factors in Brain : Regulation and Behavioral Manifestation. In: Biological Psychiatry. 2009 ; Vol. 65, No. 2. pp. 150-159.
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