2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and benzyloxycarbonylleucyl-leucyl-leucine-aldehyde

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.

Topics: Analysis of Variance; Animals; ARNTL Transcription Factors; Bicuculline; Cells, Cultured; Cerebral Cortex; Chlorocebus aethiops; Circadian Clocks; Cysteine Proteinase Inhibitors; Cytoskeletal Proteins; Dendrites; Drug Interactions; Embryo, Mammalian; Excitatory Amino Acid Antagonists; GABA-A Receptor Antagonists; Gene Expression Regulation; Green Fluorescent Proteins; GTPase-Activating Proteins; Hippocampus; Humans; Immunoprecipitation; Leupeptins; Mice; Mice, Knockout; Mutation; Neurons; Nuclear Proteins; Nuclear Receptor Subfamily 1, Group D, Member 1; Quinoxalines; Rats; RNA, Messenger; RNA, Small Interfering; Sodium Channel Blockers; Tetrodotoxin; Time Factors; Transfection; Two-Hybrid System Techniques; Valine