In contrast to FoxO1 knockout mice, reducing anxiety was not a prominent feature in mice systemically deficient of FoxO3a. Perhaps more interestingly, FoxO3a-deficient mice had significantly less immobility in the FST. The non-responsiveness to chronic imipramine treatment in FoxO3a-deficient mice provides evidence that FoxO3a may be a transcriptional mediator of the antidepressant action of imipramine. The increased phosphorylation of Akt and FoxO3a and the decreased nuclear FoxO3a after chronic imipramine treatment also suggest that the Akt signaling pathway may contribute to the delayed antidepressant effect of imipramine in which transcriptional regulation of gene expression is critical for sustained therapeutic effect (78). Furthermore, our group previously reported that glycogen synthase kinase 3 (GSK3), another major phosphorylation substrate of Akt, can be inhibited by serotonin and antidepressants that increase its inhibitory serine phosphorylation (60), and Beaulieu et. al. (79) reported that the depressive and anxiogenic behaviors of serotonin-deficient mice were blunted when GSK3 was semi-deleted. Those studies, in agreement with our findings in this study, indicate that Akt signaling pathway have an important impact in 5HT-regulated behaviors, and a coordinated regulation of substrates of the Akt-dependent signaling pathway by antidepressants may contribute to their therapeutic effects.
