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.

  • Original Article
  • Published:

Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits

Molecular Psychiatry volume 19, pages 1193–1200 (2014)Cite this article

Subjects

Abstract

Alterations of the dopaminergic system are associated with the cognitive and functional dysfunctions that characterize complex neuropsychiatric disorders. We modeled a dysfunctional dopaminergic system using mice with targeted ablation of dopamine (DA) D2 autoreceptors in mesencephalic dopaminergic neurons. Loss of D2 autoreceptors abolishes D2-mediated control of DA synthesis and release. Here, we show that this mutation leads to a profound alteration of the genomic landscape of neurons receiving dopaminergic afferents at distal sites, specifically in the prefrontal cortex. Indeed, we observed a remarkable downregulation of gene expression in this area of ~2000 genes, which involves a widespread increase in the histone repressive mark H3K9me2/3. This reprogramming process is coupled to psychotic-like behaviors in the mutant mice. Importantly, chronic treatment with a DA agonist can revert the genomic phenotype. Thus, cortical neurons undergo a profound epigenetic reprogramming in response to dysfunctional D2 autoreceptor signaling leading to altered DA levels, a process that may underlie a number of neuropsychiatric disorders.

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
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Jaenisch R, Bird A . Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33 (Suppl): 245–254.

    Article  CAS  Google Scholar 

  2. Borrelli E, Nestler EJ, Allis CD, Sassone-Corsi P . Decoding the epigenetic language of neuronal plasticity. Neuron 2008; 60: 961–974.

    Article  CAS  Google Scholar 

  3. Howes OD, Kapur S . The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 2009; 35: 549–562.

    Article  Google Scholar 

  4. Kuepper R, Skinbjerg M, Abi-Dargham A . The dopamine dysfunction in schizophrenia revisited: new insights into topography and course. Handb Exp Pharmacol 2012; 212: 1–26.

    Article  CAS  Google Scholar 

  5. Lyon GJ, Abi-Dargham A, Moore H, Lieberman JA, Javitch JA, Sulzer D . Presynaptic regulation of dopamine transmission in schizophrenia. Schizophr Bull 2011; 37: 108–117.

    Article  Google Scholar 

  6. Miyake N, Thompson J, Skinbjerg M, Abi-Dargham A . Presynaptic dopamine in schizophrenia. CNS Neurosci Ther 2011; 17: 104–109.

    Article  CAS  Google Scholar 

  7. Heinz A, Romero B, Gallinat J, Juckel G, Weinberger DR . Molecular brain imaging and the neurobiology and genetics of schizophrenia. Pharmacopsychiatry 2003; 36 (Suppl 3): S152–S157.

    CAS  Google Scholar 

  8. Howes O, Bose S, Turkheimer F, Valli I, Egerton A, Stahl D, et al. Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study. Mol Psychiatry 2011; 16: 885–886.

    Article  CAS  Google Scholar 

  9. Howes OD, Egerton A, Allan V, McGuire P, Stokes P, Kapur S . Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging. Curr Pharm Des 2009; 15: 2550–2559.

    Article  CAS  Google Scholar 

  10. Bertolino A, Knable MB, Saunders RC, Callicott JH, Kolachana B, Mattay VS, et al. The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia. Biol Psychiatry 1999; 45: 660–667.

    Article  CAS  Google Scholar 

  11. Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, et al. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002; 5: 267–271.

    Article  CAS  Google Scholar 

  12. Rice ME, Patel JC, Cragg SJ . Dopamine release in the basal ganglia. Neuroscience 2011; 198: 112–137.

    Article  CAS  Google Scholar 

  13. Rouge-Pont F, Usiello A, Benoit-Marand M, Gonon F, Piazza PV, Borrelli E . Changes in extracellular dopamine induced by morphine and cocaine: crucial control by D2 receptors. J Neurosci 2002; 22: 3293–3301.

    Article  CAS  Google Scholar 

  14. Benoit-Marand M, Borrelli E, Gonon F . Inhibition of dopamine release via presynaptic D2 receptors: time course and functional characteristics in vivo. J Neurosci 2001; 21: 9134–9141.

    Article  CAS  Google Scholar 

  15. Anzalone A, Lizardi-Ortiz JE, Ramos M, De Mei C, Hopf FW, Iaccarino C, et al. Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J Neurosci 2012; 32: 9023–9034.

    Article  CAS  Google Scholar 

  16. Jasencakova Z, Scharf AN, Ask K, Corpet A, Imhof A, Almouzni G, et al. Replication stress interferes with histone recycling and predeposition marking of new histones. Mol Cell 2010; 37: 736–743.

    Article  CAS  Google Scholar 

  17. Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald DE, Truong HT, et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 2005; 48: 303–314.

    Article  CAS  Google Scholar 

  18. Paylor R, Crawley JN . Inbred strain differences in prepulse inhibition of the mouse startle response. Psychopharmacology 1997; 132: 169–180.

    Article  CAS  Google Scholar 

  19. Errico F, Rossi S, Napolitano F, Catuogno V, Topo E, Fisone G, et al. D-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801. J Neurosci 2008; 28: 10404–10414.

    Article  CAS  Google Scholar 

  20. Wood MA, Kaplan MP, Brensinger CM, Guo W, Abel T . Ubiquitin C-terminal hydrolase L3 (Uchl3) is involved in working memory. Hippocampus 2005; 15: 610–621.

    Article  CAS  Google Scholar 

  21. Maze I, Noh KM, Allis CD . Histone regulation in the CNS: basic principles of epigenetic plasticity. Neuropsychopharmacology 2013; 38: 3–22.

    Article  CAS  Google Scholar 

  22. Akbarian S, Huang HS . Epigenetic regulation in human brain—focus on histone lysine methylation. Biol Psychiatry 2009; 65: 198–203.

    Article  CAS  Google Scholar 

  23. Russo SJ, Nestler EJ . The brain reward circuitry in mood disorders. Nat Rev Neurosci 2013; 14: 609–625.

    Article  CAS  Google Scholar 

  24. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, et al. High-resolution profiling of histone methylations in the human genome. Cell 2007; 129: 823–837.

    Article  CAS  Google Scholar 

  25. Fodor BD, Kubicek S, Yonezawa M, O'Sullivan RJ, Sengupta R, Perez-Burgos L, et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev 2006; 20: 1557–1562.

    Article  CAS  Google Scholar 

  26. Rojas P, Joodmardi E, Hong Y, Perlmann T, Ogren SO . Adult mice with reduced Nurr1 expression: an animal model for schizophrenia. Mol Psychiatry 2007; 12: 756–766.

    Article  CAS  Google Scholar 

  27. Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA . Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 2004; 36: 131–137.

    Article  CAS  Google Scholar 

  28. Arguello PA, Gogos JA . Modeling madness in mice: one piece at a time. Neuron 2006; 52: 179–196.

    Article  CAS  Google Scholar 

  29. Jones CA, Watson DJ, Fone KC . Animal models of schizophrenia. Br J Pharmacol 2011; 164: 1162–1194.

    Article  CAS  Google Scholar 

  30. Seeman P . All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2(high) receptors. CNS Neurosci Ther 2011; 17: 118–132.

    Article  CAS  Google Scholar 

  31. Yoon T, Okada J, Jung MW, Kim JJ . Prefrontal cortex and hippocampus subserve different components of working memory in rats. Learn Mem 2008; 15: 97–105.

    Article  Google Scholar 

  32. Papaleo F, Yang F, Garcia S, Chen J, Lu B, Crawley JN, et al. Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry 2012; 17: 85–98.

    Article  CAS  Google Scholar 

  33. Goto Y, Grace AA . The dopamine system and the pathophysiology of schizophrenia: a basic science perspective. Int Rev Neurobiol 2007; 78: 41–68.

    Article  CAS  Google Scholar 

  34. Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 2006; 125: 467–481.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Drs F Torri and C De Mei for assistance and interest in the initial phase of this study; Dr P Sassone-Corsi for critical discussions and reading of the manuscript. This work was supported by NIH Grant DA024689 and INSERM-44790 (to EB).

Author information

Author notes

  1. K Brami-Cherrier, A Anzalone and M Ramos: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics and INSERM/UCI U904, University of California Irvine, Irvine, CA, USA,

    K Brami-Cherrier, A Anzalone, M Ramos & E Borrelli

  2. Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA,

    K Brami-Cherrier, A Anzalone, M Ramos, F Macciardi, A Imhof & E Borrelli

  3. Munich Cluster for Systems Neurology (SyNergy) and Adolf-Butenandt Institute, Ludwig Maximilians University of Munich, Munich, Germany

    I Forne & A Imhof

  4. Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA

    F Macciardi

Authors
  1. K Brami-Cherrier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Anzalone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Forne
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F Macciardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Imhof
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Borrelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Borrelli.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brami-Cherrier, K., Anzalone, A., Ramos, M. et al. Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits. Mol Psychiatry 19, 1193–1200 (2014). https://doi.org/10.1038/mp.2014.67

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2014.67

This article is cited by

Search

Advanced search

Quick links