The findings that enhancing brain serotonergic activity by d-fenfluramine treatment increases the inhibitory phosphorylation of FoxO1 and FoxO3a in several regions of mouse brain conform with findings in C. elegans by Liang et al. (57), and we confirm that serotonin can regulate FoxO transcription factors in mammalian brain. Although serotonin often is not considered as a primary activator of the PI3K/Akt signaling pathway, several studies in cultured cells and in invertebrates have shown that stimulation of serotonin receptors can result in phosphorylation and activation of Akt (57, 65, 66). The results shown in this study support the conclusion that enhancing serotonin activity exhibits a regulatory effect in Akt-regulated FoxO1 and FoxO3a in brain. Although the specific serotonin receptors mediating this effect remain to be identified, our observations imply that brain FoxOs are important transcription factors on which signals from serotonergic neurotransmission and neurotrophic activity converge. In our experiments, the PI3K inhibitor LY294002 partially reduced the effect of d-fenfluramine. It is possible that the low dose LY294002 is not sufficient to penetrate into all brain areas, but we do not rule
