title: A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα.
abstract: Oligophrenin-1 regulates dendritic spine morphology in the brain. Mutations in the oligophrenin-1 gene (OPHN1) cause intellectual disability. We discovered a previously unknown partner of oligophrenin-1, Rev-erbα, a nuclear receptor that represses the transcription of circadian oscillators. We found that oligophrenin-1 interacts with Rev-erbα in the mouse brain, causing it to locate to dendrites, reducing its repressor activity and protecting it from degradation. Our results indicate the presence of a circadian oscillator in the hippocampus, involving the clock gene Bmal1 (also known as Arntl), that is modulated by Rev-erbα and requires oligophrenin-1 for normal oscillation. We also found that synaptic activity induced Rev-erbα localization to dendrites and spines, a process that is mediated by AMPA receptor activation and requires oligophrenin-1. Our data reveal new interactions between synaptic activity and circadian oscillators, and delineate a new means of communication between nucleus and synapse that may provide insight into normal plasticity and the etiology of intellectual disability.
authors.affiliation: Consiglio Nazionale delle Ricerche (CNR) Institute of Neuroscience, Department of Pharmacology, University of Milan, Milan, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Valnegri
authors.forename: Malik
authors.initials: M
authors.lastname: Khelfaoui
authors.forename: Olivier
authors.initials: O
authors.lastname: Dorseuil
authors.forename: Silvia
authors.initials: S
authors.lastname: Bassani
authors.forename: Celine
authors.initials: C
authors.lastname: Lagneaux
authors.forename: Antonella
authors.initials: A
authors.lastname: Gianfelice
authors.forename: Roberta
authors.initials: R
authors.lastname: Benfante
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
authors.forename: Carlo
authors.initials: C
authors.lastname: Sala
authors.forename: Maria
authors.initials: M
authors.lastname: Passafaro
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002522:Chlorocebus aethiops; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D047468:Immunoprecipitation; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D020798:Two-Hybrid System Techniques; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D056930:ARNTL Transcription Factors; D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D020690:GTPase-Activating Proteins; D007976:Leupeptins; C064353:NR1D1 protein, human; D009687:Nuclear Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; C111952:OPHN1 protein, human; D011810:Quinoxalines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D026941:Sodium Channel Blockers; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D001640:Bicuculline