Molecular mechanism underlying premenstrual dysphoric disorder

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When we examined menstrual variations of circadian sleep rhythms in 20 healthy and 20 PMDD(Premenstrual dysphoric disorder) subjects, 2 PMDD subjects showed APSS(alternative phase shift syndrome) but none of the healthy subjects showed APSS, suggesting that PMDD may be involved in APSS. In order to investigate the mechanisms underlying APSS, we examined the effects of estrogen (E)on the circadian rhythms in clock genes (Per1,Per2) in the suprachiasmatic nucleus (SCN), the site of circadian clock. E advanced the phase of Per2 rhythms but not Per1 rhythms. The amplitude of Per2 was decreased by E but that of Per1 was not affected. When we examined the subtype of E receptor (R) in the SCN, only ER-□□was proved to be expressed in the SCN. We examined the subtype of the steroid receptor coactivator (SRC1,2,3), which enhances the transcriptional activity of nuclear recptors, because E and ER complexes regulate the transcription of a target gene by binding to ERE of the gene under the influence of coactivators. Only SRC-1 was proved to be specifically expressed in the SCN. We determined whether SRC-1 binds to CLOCK and/or BMAL because CLOCK and BMAL are positive-regulators of clock genes. We found that SRC-1 binds to CLOCK, so that E regulates clock genes via SRC-1.