Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Neuroscience volume 14, pages 1293–1301 (2011)Cite this article

Subjects

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Oligophrenin-1 interacts with Rev-erbα in yeast two-hybrid system, COS7 cells and in neurons.
Figure 2: Oligophrenin-1 reduces transcriptional repression by Rev-erbα.
Figure 3: Altered circadian expression of Rev-erbα and clock gene mRNAs in Ophn1−/− mice.
Figure 4: Accumulation of Rev-erbα in the dendrites and spines induced by overexpression of oligophrenin-1 in neurons.
Figure 5: Synaptic activity induces localization of Rev-erbα at synapses.
Figure 6: Oligophrenin-1 is required for the synaptic activity–induced localization of endogenous Rev-erbα in dendrites.
Figure 7: Oligophrenin-1 interaction is required for Rev-erbα mRNA expression in hippocampal neurons.

Similar content being viewed by others

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.

References

  1. Gécz, J., Shoubridge, C. & Corbett, M. The genetic landscape of intellectual disability arising from chromosome X. Trends Genet. 25, 308–316 (2009).

    Article  Google Scholar 

  2. Kaufman, L., Ayub, M. & Vincent, J.B . The genetic basis of non-syndromic intellectual disability: a review. J. Neurodev. Disord. 2, 182–209 (2010).

    Article  Google Scholar 

  3. Ropers, H.H. Genetics of early onset cognitive impairment. Annu. Rev. Genomics Hum. Genet. 11, 161–187 (2010).

    Article  CAS  Google Scholar 

  4. Ropers, H.H. & Hamel, B.C. X-linked mental retardation. Nat. Rev. Genet. 6, 46–57 (2005).

    Article  CAS  Google Scholar 

  5. Fauchereau, F. et al. The RhoGAP activity of OPHN1, a new F-actin-binding protein, is negatively controlled by its amino-terminal domain. Mol. Cell. Neurosci. 23, 574–586 (2003).

    Article  CAS  Google Scholar 

  6. Govek, E.E. et al. The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nat. Neurosci. 7, 364–372 (2004).

    Article  CAS  Google Scholar 

  7. Khelfaoui, M. et al. Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. J. Neurosci. 27, 9439–9450 (2007).

    Article  CAS  Google Scholar 

  8. Billuart, P. et al. Oligophrenin 1 encodes a rho-GAP protein involved in X-linked mental retardation. Nature 392, 923–926 (1998).

    Article  CAS  Google Scholar 

  9. Tentler, D. et al. Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia. Eur. J. Hum. Genet. 7, 541–548 (1999).

    Article  CAS  Google Scholar 

  10. Philip, N. et al. Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia. J. Med. Genet. 40, 441–446 (2003).

    Article  CAS  Google Scholar 

  11. Bergmann, C. et al. Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain 126, 1537–1544 (2003).

    Article  Google Scholar 

  12. Nakano-Kobayashi, A., Kasri, N.N., Newey, S.E. & Van Aelst, L. The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1. Curr. Biol. 19, 1133–1139 (2009).

    Article  CAS  Google Scholar 

  13. Xiao, B., Tu, J.C. & Worley, P.F. Homer: a link between neural activity and glutamate receptor function. Curr. Opin. Neurobiol. 10, 370–374 (2000).

    Article  CAS  Google Scholar 

  14. Fagni, L., Chavis, P., Ango, F. & Bockaert, J. Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels in neurons. Trends Neurosci. 23, 80–88 (2000).

    Article  CAS  Google Scholar 

  15. Sala, C. et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31, 115–130 (2001).

    Article  CAS  Google Scholar 

  16. Khelfaoui, M. et al. Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation. Hum. Mol. Genet. 18, 2575–2583 (2009).

    Article  CAS  Google Scholar 

  17. Preitner, N. et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002).

    Article  CAS  Google Scholar 

  18. Raghuram, S. et al. Identification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβ. Nat. Struct. Mol. Biol. 14, 1207–1213 (2007).

    Article  CAS  Google Scholar 

  19. Chomez, P. et al. Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbA(α) orphan receptor. Development 127, 1489–1498 (2000).

    CAS  PubMed  Google Scholar 

  20. Harding, H.P. & Lazar, M.A. The orphan receptor Rev-ErbA α activates transcription via a novel response element. Mol. Cell. Biol. 13, 3113–3121 (1993).

    Article  CAS  Google Scholar 

  21. Adelmant, G., Begue, A., Stehelin, D. & Laudet, V. A functional Rev-erb α responsive element located in the human Rev-erb α promoter mediates a repressing activity. Proc. Natl. Acad. Sci. USA 93, 3553–3558 (1996).

    Article  CAS  Google Scholar 

  22. Yin, L., Wang, J., Klein, P.S. & Lazar, M.A. Nuclear receptor Rev-erbα is a critical lithium-sensitive component of the circadian clock. Science 311, 1002–1005 (2006).

    Article  CAS  Google Scholar 

  23. Flavell, S.W. & Greenberg, M.E. Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu. Rev. Neurosci. 31, 563–590 (2008).

    Article  CAS  Google Scholar 

  24. Thompson, K.R. et al. Synapse to nucleus signaling during long-term synaptic plasticity; a role for the classical active nuclear import pathway. Neuron 44, 997–1009 (2004).

    CAS  Google Scholar 

  25. An, J.J. et al. Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134, 175–187 (2008).

    Article  CAS  Google Scholar 

  26. Ferkany, J.W., Zaczek, R. & Coyle, J.T. The mechanism of kainic acid neurotoxicity. Nature 308, 561–562 (1984).

    Article  CAS  Google Scholar 

  27. Zaczek, R., Nelson, M. & Coyle, J.T. Kainic acid neurotoxicity and seizures. Neuropharmacology 20, 183–189 (1981).

    Article  CAS  Google Scholar 

  28. Pardee, K.I. et al. The structural basis of gas-responsive transcription by the human nuclear hormone receptor REV-ERBβ. PLoS Biol. 7, e43 (2009).

    Article  Google Scholar 

  29. Ueda, H.R. et al. A transcription factor response element for gene expression during circadian night. Nature 418, 534–539 (2002).

    Article  CAS  Google Scholar 

  30. Lamont, E.W., Robinson, B., Stewart, J. & Amir, S. The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2. Proc. Natl. Acad. Sci. USA 102, 4180–4184 (2005).

    Article  CAS  Google Scholar 

  31. Wakamatsu, H. et al. Restricted feeding–induced anticipatory activity rhythm is associated with a phase-shift of the expression of mPer1 and mPer2 mRNA in the cerebral cortex and hippocampus but not in the suprachiasmatic nucleus of mice. Eur. J. Neurosci. 13, 1190–1196 (2001).

    Article  CAS  Google Scholar 

  32. Chaudhury, D., Loh, D.H., Dragich, J.M., Hagopian, A. & Colwell, C.S. Select cognitive deficits in vasoactive intestinal peptide deficient mice. BMC Neurosci. 9, 63 (2008).

    Article  Google Scholar 

  33. Abraham, U., Prior, J.L., Granados-Fuentes, D., Piwnica-Worms, D.R. & Herzog, E.D. Independent circadian oscillations of Period1 in specific brain areas in vivo and in vitro. J. Neurosci. 25, 8620–8626 (2005).

    Article  CAS  Google Scholar 

  34. Mendoza, J., Pevet, P., Felder-Schmittbuhl, M.P., Bailly, Y. & Challet, E. The cerebellum harbors a circadian oscillator involved in food anticipation. J. Neurosci. 30, 1894–1904 (2010).

    Article  CAS  Google Scholar 

  35. Abe, H., Honma, S., Namihira, M., Masubuchi, S. & Honma, K. Behavioral rhythm splitting in the CS mouse is related to clock gene expression outside the suprachiasmatic nucleus. Eur. J. Neurosci. 14, 1121–1128 (2001).

    Article  CAS  Google Scholar 

  36. Gilestro, G.F., Tononi, G. & Cirelli, C. Widespread changes in synaptic markers as a function of sleep and wakefulness in Drosophila. Science 324, 109–112 (2009).

    Article  CAS  Google Scholar 

  37. Hastings, M.H., Reddy, A.B. & Maywood, E.S. A clockwork web: circadian timing in brain and periphery, in health and disease. Nat. Rev. Neurosci. 4, 649–661 (2003).

    Article  CAS  Google Scholar 

  38. Triqueneaux, G. et al. The orphan receptor Rev-erbα gene is a target of the circadian clock pacemaker. J. Mol. Endocrinol. 33, 585–608 (2004).

    Article  CAS  Google Scholar 

  39. Nadif Kasri, N., Nakano-Kobayashi, A., Malinow, R., Li, B. & Van Aelst, L. The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors. Genes Dev. 23, 1289–1302 (2009).

    Article  Google Scholar 

  40. Vyazovskiy, V.V., Cirelli, C., Pfister-Genskow, M., Faraguna, U. & Tononi, G. Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nat. Neurosci. 11, 200–208 (2008).

    Article  CAS  Google Scholar 

  41. Donlea, J.M., Ramanan, N. & Shaw, P.J. Use-dependent plasticity in clock neurons regulates sleep need in Drosophila. Science 324, 105–108 (2009).

    Article  CAS  Google Scholar 

  42. Flora, A. et al. Sp proteins and Phox2b regulate the expression of the human Phox2a gene. J. Neurosci. 21, 7037–7045 (2001).

    Article  CAS  Google Scholar 

  43. Battaglioli, E. et al. Expression and transcriptional regulation of the human alpha3 neuronal nicotinic receptor subunit in T lymphocyte cell lines. J. Neurochem. 71, 1261–1270 (1998).

    Article  CAS  Google Scholar 

  44. Sala, C., Rudolph-Correia, S. & Sheng, M. Developmentally regulated NMDA receptor–dependent dephosphorylation of cAMP response element-binding protein (CREB) in hippocampal neurons. J. Neurosci. 20, 3529–3536 (2000).

    Article  CAS  Google Scholar 

  45. Passafaro, M., Nakagawa, T., Sala, C. & Sheng, M. Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2. Nature 424, 677–681 (2003).

    Article  CAS  Google Scholar 

  46. Saglietti, L. et al. Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron 54, 461–477 (2007).

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

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

Authors
  1. Pamela Valnegri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Malik Khelfaoui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olivier Dorseuil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvia Bassani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Celine Lagneaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonella Gianfelice
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Roberta Benfante
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jamel Chelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pierre Billuart
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Carlo Sala
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maria Passafaro
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Maria Passafaro.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 4472 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Valnegri, P., Khelfaoui, M., Dorseuil, O. et al. A circadian clock in hippocampus is regulated by interaction between oligophrenin-1 and Rev-erbα. Nat Neurosci 14, 1293–1301 (2011). https://doi.org/10.1038/nn.2911

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing