Background
The transcription factor FoxO3a is highly expressed in brain, but little is known
about the response of FoxO3a to behavioral stress and its impact in the associated
behavioral changes.
Methods
We tested the response of brain FoxO3a in the learned helplessness (LH) paradigm and
tested signaling pathways that mediate the response of FoxO3a.
Results
A single session of inescapable shocks (IES) in mice reduced FoxO3a phosphorylation
at the Akt-regulating serine/threonine residues and induced prolonged nuclear accumulation
of FoxO3a in the cerebral cortex, both indicating activation of FoxO3a in brain. The
response of FoxO3a is accompanied by a transient inactivation of Akt and a prolonged
activation of glycogen synthase kinase-3beta (GSK3β). Noticeably, FoxO3a formed a
protein complex with GSK3β in the cerebral cortex, and the interaction between the
two proteins was stronger in IES-treated mice. Inhibition of glycogen synthase kinase-3
was able to abolish IES-induced LH behavior, disrupt IES-induced GSK3β-FoxO3a interaction,
and reduce nuclear FoxO3a accumulation. In vitro approaches further revealed that
the interaction between GSK3β and FoxO3a was strongest when both were active; FoxO3a
was phosphorylated by recombinant GSK3β; and glycogen synthase kinase-3 inhibitors
effectively reduced FoxO3a transcriptional activity. Importantly, IES-induced LH behavior
was markedly diminished in FoxO3a-deficient mice that had minimal FoxO3a expression
and reduced levels of FoxO3a-inducible genes.
Conclusions
FoxO3a is activated in response to IES by interacting with GSK3β, and inhibition of
GSK3β or reducing FoxO3a expression promotes resistance to stress-induced behavioral
disturbance by disrupting this signaling mechanism.
Key Words
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Article info
Publication history
Published online: October 07, 2011
Accepted:
August 25,
2011
Received in revised form:
August 22,
2011
Received:
May 24,
2011
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
