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A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα

Nature Neuroscience 14, 1293–1301 (2011) | Download Citation

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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.

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Change history

  • 11 September 2011

    In the version of this article initially published online, affiliation 4 was misnumbered as 5, 5 was misnumbered as 6 and 6 was misnumbered as 4. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

The authors thank D. Ward for assisting with the manuscript. The authors thank E. Challet, D. Ciocca and S. Reibel-Foisset for advice with the circadian experiments. M.P. was supported by Telethon Italy (S01014TELU), Fondazione Cariplo (2008-2318), Fondazione Mariani, Project TerDisMental, ID 16983 - Rif. SAL-50. C.S. was supported by Telethon-Italy grant GGP09196, Fondazione CARIPLO project no. 2009.264, Ricerca Scientifica a Tema Libero (RSTL) Consiglio Nazionale delle Ricerche (CNR), Regione Lombardia Project no. SAL-50-16983 TERDISMENTAL and an Italian Institute of Technology Seed Grant. P.B., O.D. and J.C. are supported by the French National Research Agency (ANR-06-Neuro-003-02, ANR-08-MNPS-037-04), European Union (Gencodys, FP7 241995), Fondation Jérôme Lejeune and INSERM. C.L. was supported by the “Fondation pour La Recherche Médicale”.

Author information

Affiliations

  1. Consiglio Nazionale delle Ricerche (CNR) Institute of Neuroscience, Department of Pharmacology, University of Milan, Milan, Italy.

    • Pamela Valnegri
    • , Silvia Bassani
    • , Antonella Gianfelice
    • , Roberta Benfante
    • , Carlo Sala
    •  & Maria Passafaro

  2. Dulbecco Telethon Institute, Milan, Italy.

    • Pamela Valnegri
    • , Silvia Bassani
    •  & Maria Passafaro

  3. INSERM, U1016, Institut Cochin, Paris, France.

    • Malik Khelfaoui
    • , Olivier Dorseuil
    • , Celine Lagneaux
    • , Jamel Chelly
    •  & Pierre Billuart

  4. Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France.

    • Malik Khelfaoui
    • , Olivier Dorseuil
    • , Celine Lagneaux
    • , Jamel Chelly
    •  & Pierre Billuart

  5. University of Paris Descartes, Paris, France.

    • Malik Khelfaoui
    • , Olivier Dorseuil
    • , Celine Lagneaux
    • , Jamel Chelly
    •  & Pierre Billuart

  6. Neuromuscular Diseases and Neuroimmunology, Neurological Institute and Foundation “Carlo Besta”, Milan, Italy.

    • Carlo Sala

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Contributions

P.V. conducted all the experiments in COS7 cells, in hippocampal neurons and in vivo. M.K., O.D. and C.L. conducted the experiments on circadian cycle. S.B. and A.G. prepared mutants for yeast two-hybrid screening. R.B. supervised the experiments with luciferase assays. J.C., P.B. and C.S. supervised the project. M.P. wrote the manuscript and supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Maria Passafaro.

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DOI

https://doi.org/10.1038/nn.2911