Title | Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Polter A, Yang S, Zmijewska AA, van Groen T, Paik J-H, DePinho RA, Peng SL, Jope RS, Li X |
Journal | Biol Psychiatry |
Volume | 65 |
Issue | 2 |
Pagination | 150-9 |
Date Published | 2009 Jan 15 |
ISSN | 1873-2402 |
Keywords | Affect, Analysis of Variance, Animals, Antidepressive Agents, Tricyclic, Anxiety, Behavior, Animal, Brain, Depression, Exploratory Behavior, Female, Fenfluramine, Forkhead Box Protein O1, Forkhead Box Protein O3, Forkhead Transcription Factors, Gene Expression Regulation, Imipramine, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phosphorylation, Serotonin, Serotonin Agents |
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. |
DOI | 10.1016/j.biopsych.2008.08.005 |
Alternate Journal | Biol Psychiatry |
PubMed ID | 18823877 |
PubMed Central ID | PMC2630515 |
Grant List | P30 NS047466 / NS / NINDS NIH HHS / United States MH 73723 / MH / NIMH NIH HHS / United States P30 NS057098 / NS / NINDS NIH HHS / United States K08 MH064555-05 / MH / NIMH NIH HHS / United States AI 57571 / AI / NIAID NIH HHS / United States R37 CA084628 / CA / NCI NIH HHS / United States R01 MH073723-03 / MH / NIMH NIH HHS / United States R01 AI057571 / AI / NIAID NIH HHS / United States NS 47466 / NS / NINDS NIH HHS / United States K08 MH064555 / MH / NIMH NIH HHS / United States R01 MH073723-02 / MH / NIMH NIH HHS / United States R01 MH073723 / MH / NIMH NIH HHS / United States K08 MH064555-03 / MH / NIMH NIH HHS / United States R56 MH038752 / MH / NIMH NIH HHS / United States CA 84628 / CA / NCI NIH HHS / United States MH 38752 / MH / NIMH NIH HHS / United States NS 57098 / NS / NINDS NIH HHS / United States R01 CA084628 / CA / NCI NIH HHS / United States R01 MH038752 / MH / NIMH NIH HHS / United States K08 MH064555-04 / MH / NIMH NIH HHS / United States R01 MH038752-24S1 / MH / NIMH NIH HHS / United States MH 64555 / MH / NIMH NIH HHS / United States |
Related Faculty:
Ji-Hye Paik, Ph.D.