Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation.
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.
Polter
Abigail
A
Department of Psychiatry, University of Alabama at Birmingham,1075 Sparks Center, 1720 7th Avenue South, Birmingham, AL35294-0017, USA.
Yang
Sufen
S
Zmijewska
Anna A
AA
van Groen
Thomas
T
Paik
Ji-Hye
JH
Depinho
Ronald A
RA
Peng
Stanford L
SL
Jope
Richard S
RS
Li
Xiaohua
X
D000339:Affect / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001007:Anxiety / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D018490:Serotonin Agents; D005277:Fenfluramine; D012701:Serotonin; D007099:Imipramine