title: Ketamine influences CLOCK:BMAL1 function leading to altered circadian gene expression.
abstract: Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.
authors: Center for Epigenetics and Metabolism, School of Medicine, University of California Irvine, Irvine, California, United States of America.
authors: Marina M
authors: MM
authors: Bellet
authors: Marquis P
authors: MP
authors: Vawter
authors: Blynn G
authors: BG
authors: Bunney
authors: William E
authors: WE
authors: Bunney
authors: Paolo
authors: P
authors: Sassone-Corsi
mesh_terms: D000818:Animals; D056926:CLOCK Proteins / Q000187:drug effects / Q000502:physiology*; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000187:drug effects / Q000502:physiology; D056931:Cryptochromes; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology*; D007649:Ketamine / Q000494:pharmacology*; D051379:Mice; D056950:Period Circadian Proteins / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000502:physiology*; D013045:Species Specificity
chemical_list: D056925:Circadian Rhythm Signaling Peptides and Proteins; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D018691:Excitatory Amino Acid Antagonists; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D007649:Ketamine; D056926:CLOCK Proteins; C529384:Parp9 protein, mouse; D011065:Poly(ADP-ribose) Polymerases