Contributed by Louis J. Ptáček, January 4, 2016 (sent for review October 5, 2015; reviewed by Nelson B. Freimer, Daniel H. Geschwind, and Emmanuel J. M. Mignot)
It has long been thought that sleep and mood are intimately connected in humans, but at present there are no known molecular links. We identified rare variants in the PERIOD3 gene in persons with both altered sleep behavior and features of seasonal affective disorder. We show that these variants recapitulate circadian and mood phenotypes in mouse models. Although we were not able to test mood in fruit flies, we did uncover a sleep trait similar to that seen in humans in flies carrying the human variants. Our molecular studies reveal that the variants led to less stable PER3 protein and reduced the stabilizing effect of PER3 on PER1/PER2, providing a mechanistic explanation for the circadian trait.
In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.
↵1L.Z. and A.H. contributed equally to this work.
↵2Present address: Faculty of Medicine, Department of Neurology, Kinki University, 577-8502 Osaka, Japan.
Author contributions: L.Z., L.J.P., and Y.-H.F. designed research; L.Z., A.H., P.-K.H., C.R.J., N. Sakai, M.O., T.M., M.Y., N. Saigoh, K.S., S.-T.L., and K.K. performed research; Y.X. and S.N. contributed new reagents/analytic tools; L.Z., A.H., P.-K.H., C.R.J., N. Sakai, and M.O. analyzed data; and L.Z., A.H., L.J.P., and Y.-H.F. wrote the paper.
Reviewers: N.B.F., UCLA Center for Neurobehavioral Genetics; D.H.G., University of California Los Angeles; and E.J.M.M., Stanford University School of Medicine.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1600039113/-/DCSupplemental.
