Behavioral Stress-Induced Activation of FoxO3a in the Cerebral Cortex of Mice

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 (GSK3 beta). Noticeably, FoxO3a formed a protein complex with GSK3 beta 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 GSK3 beta-FoxO3a interaction, and reduce nuclear FoxO3a accumulation. In vitro approaches further revealed that the interaction between GSK3 beta and FoxO3a was strongest when both were active; FoxO3a was phosphorylated by recombinant GSK3 beta; 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 GSK3 beta, and inhibition of GSK3 beta or reducing FoxO3a expression promotes resistance to stress-induced behavioral disturbance by disrupting this signaling mechanism.