Melatonin is a well-known regulator of sleep, and its precursor, N-acetylserotonin (NAS), has become recognized as a circadian-regulated signaling molecule independent from its role in melatonin synthesis. NAS activates the neurotrophin receptor tyrosine kinase TrkB, which has been implicated in alleviating depression, a process that involves production of new neurons. Sompol et al. injected NAS into mice deficient in the NAS synthesis enzyme and showed that this promoted hippocampal cell proliferation and an increase in the number of stem cell progenitors that were positive for phosphorylated TrkB. In mice with an inhibitor-sensitive knockin of TrkB, cotreatment with the TrkB inhibitor and NAS prevented the NAS-induced increase in hippocampal cell proliferation and blocked the NAS-stimulated increase in phosphorylated TrkB and activation of downstream signaling proteins. Injection of NAS into mice deficient in endogenous NAS synthesis during only the sleeping phase of the day was sufficient to induce hippocampal cell proliferation. Twice-daily injections of NAS reversed the sleep deprivation–induced reduction in hippocampal cell proliferation, TrkB phosphorylation, and activation of downstream signaling proteins. Thus, NAS appears to signal through TrkB to mediate hippocampal cell proliferation, and targeting this pathway may be useful in ameliorating some of the effects of sleep deprivation.
P. Sompol, X. Liu, K. Baba, K. N. Paul, G. Tosini, P. M. Iuvone, K. Ye, N-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice. Proc. Natl. Acad. Sci. U.S.A. 108, 8844–8849 (2011). [Abstract] [Full Text]