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:

Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action

Abstract

To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I–V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Social interaction and avoidance after chronic social defeat and antidepressant treatments.
Figure 2: Differential regulation of Bdnf III and IV mRNA after chronic defeat stress and imipramine treatments.
Figure 3: Stable changes in histone modifications after chronic defeat stress and imipramine treatments.
Figure 4: Expressional analysis of class I and II Hdacs.
Figure 5: Viral-mediated overexpression of HDAC5 blocks the ability of chronic imipramine to reverse behavioral deficits of chronic defeat stress.

Similar content being viewed by others

References

  1. Nestler, E.J. et al. Neurobiology of depression. Neuron 34, 13–25 (2002).

    Article  CAS  Google Scholar 

  2. Manji, H.K., Drevets, W.C. & Charney, D.S. The cellular neurobiology of depression. Nat. Med. 7, 541–547 (2001).

    Article  CAS  Google Scholar 

  3. Sheline, Y.I., Gado, M.H. & Kraemer, H.C. Untreated depression and hippocampal volume loss. Am. J. Psychiatry 160, 1516–1518 (2003).

    Article  Google Scholar 

  4. Duman, R.S. Depression: a case of neuronal life and death? Biol. Psychiatry 56, 140–145 (2004).

    Article  Google Scholar 

  5. McEwen, B.S., Magarinos, A.M. & Reagan, L.P. Structural plasticity and tianeptine: cellular and molecular targets. Eur. Psychiatry 17 (suppl.), 318–330 (2002).

    Article  Google Scholar 

  6. Sapolsky, R.M. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch. Gen. Psychiatry 57, 925–935 (2000).

    Article  CAS  Google Scholar 

  7. Shirayama, Y., Chen, A.C., Nakagawa, S., Russell, D.S. & Duman, R.S. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 3251–3261 (2002).

    Article  CAS  Google Scholar 

  8. Monteggia, L.M. et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc. Natl. Acad. Sci. USA 101, 10827–10832 (2004).

    Article  CAS  Google Scholar 

  9. Smith, M.A., Makino, S., Kvetnansky, R. & Post, R.M. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 15, 1768–1777 (1995).

    Article  CAS  Google Scholar 

  10. Nibuya, M., Morinobu, S. & Duman, R.S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 15, 7539–7547 (1995).

    Article  CAS  Google Scholar 

  11. Schaaf, M.J., de Jong, J., de Kloet, E.R. & Vreugdenhil, E. Downregulation of BDNF mRNA and protein in the rat hippocampus by corticosterone. Brain Res. 813, 112–120 (1998).

    Article  CAS  Google Scholar 

  12. Pizarro, J.M. et al. Acute social defeat reduces neurotrophin expression in brain cortical and subcortical areas in mice. Brain Res. 1025, 10–20 (2004).

    Article  CAS  Google Scholar 

  13. Russo-Neustadt, A., Beard, R.C. & Cotman, C.W. Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression. Neuropsychopharmacology 21, 679–682 (1999).

    Article  CAS  Google Scholar 

  14. Timmusk, T. et al. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10, 475–489 (1993).

    Article  CAS  Google Scholar 

  15. Tapia-Arancibia, L., Rage, F., Givalois, L. & Arancibia, S. Physiology of BDNF: focus on hypothalamic function. Front. Neuroendocrinol. 25, 77–107 (2004).

    Article  CAS  Google Scholar 

  16. Felsenfeld, G. & Groudine, M. Controlling the double helix. Nature 421, 448–453 (2003).

    Article  Google Scholar 

  17. Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  Google Scholar 

  18. Lachner, M., O'Sullivan, R.J. & Jenuwein, T. An epigenetic road map for histone lysine methylation. J. Cell Sci. 116, 2117–2124 (2003).

    Article  CAS  Google Scholar 

  19. Lachner, M. & Jenuwein, T. The many faces of histone lysine methylation. Curr. Opin. Cell Biol. 14, 286–298 (2002).

    Article  CAS  Google Scholar 

  20. Lunyak, V.V. et al. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298, 1747–1752 (2002).

    Article  CAS  Google Scholar 

  21. Hsieh, J. & Gage, F.H. Epigenetic control of neural stem cell fate. Curr. Opin. Genet. Dev. 14, 461–469 (2004).

    Article  CAS  Google Scholar 

  22. Steffan, J.S. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743 (2001).

    Article  CAS  Google Scholar 

  23. Hockly, E. et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc. Natl. Acad. Sci. USA 100, 2041–2046 (2003).

    Article  CAS  Google Scholar 

  24. Hoshino, M. et al. Histone deacetylase activity is retained in primary neurons expressing mutant huntingtin protein. J. Neurochem. 87, 257–267 (2003).

    Article  CAS  Google Scholar 

  25. Etchegaray, J.P., Lee, C., Wade, P.A. & Reppert, S.M. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421, 177–182 (2003).

    Article  CAS  Google Scholar 

  26. Huang, Y., Doherty, J.J. & Dingledine, R. Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus. J. Neurosci. 22, 8422–8428 (2002).

    Article  CAS  Google Scholar 

  27. Tsankova, N.M., Kumar, A. & Nestler, E.J. Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J. Neurosci. 24, 5603–5610 (2004).

    Article  CAS  Google Scholar 

  28. Yeh, S.H., Lin, C.H. & Gean, P.W. Acetylation of nuclear factor-kappaB in rat amygdala improves long-term but not short-term retention of fear memory. Mol. Pharmacol. 65, 1286–1292 (2004).

    Article  CAS  Google Scholar 

  29. Levenson, J.M. et al. Regulation of histone acetylation during memory formation in the hippocampus. J. Biol. Chem. 279, 40545–40559 (2004).

    Article  CAS  Google Scholar 

  30. Korzus, E., Rosenfeld, M.G. & Mayford, M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42, 961–972 (2004).

    Article  CAS  Google Scholar 

  31. Levenson, J.M. & Sweatt, J.D. Epigenetic mechanisms in memory formation. Nat. Rev. Neurosci. 6, 108–118 (2005).

    Article  CAS  Google Scholar 

  32. Guan, Z. et al. Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell 111, 483–493 (2002).

    Article  CAS  Google Scholar 

  33. Kumar, A. et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005).

    Article  CAS  Google Scholar 

  34. Buwalda, B. et al. Long-term effects of social stress on brain and behavior: a focus on hippocampal functioning. Neurosci. Biobehav. Rev. 29, 83–97 (2005).

    Article  Google Scholar 

  35. Koolhaas, J.M., De Boer, S.F., De Rutter, A.J., Meerlo, P. & Sgoifo, A. Social stress in rats and mice. Acta Physiol. Scand. Suppl. 640, 69–72 (1997).

    CAS  PubMed  Google Scholar 

  36. Fuchs, E. & Flugge, G. Chronic social stress: effects on limbic brain structures. Physiol. Behav. 79, 417–427 (2003).

    Article  CAS  Google Scholar 

  37. Miczek, K.A., Covington, H.E. III, Nikulina, E.M. Jr. & Hammer, R.P. Aggression and defeat: persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits. Neurosci. Biobehav. Rev. 27, 787–802 (2004).

    Article  CAS  Google Scholar 

  38. Fuchs, E. & Flugge, G. Social stress in tree shrews: effects on physiology, brain function, and behavior of subordinate individuals. Pharmacol. Biochem. Behav. 73, 247–258 (2002).

    Article  CAS  Google Scholar 

  39. Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).

    Article  CAS  Google Scholar 

  40. Dias, B.G., Banerjee, S.B., Duman, R.S. & Vaidya, V.A. Differential regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain. Neuropharmacology 45, 553–563 (2003).

    Article  CAS  Google Scholar 

  41. Turner, B.M. Cellular memory and the histone code. Cell 111, 285–291 (2002).

    Article  CAS  Google Scholar 

  42. Clark, M.S. et al. Overexpression of 5–HT1B receptor in dorsal raphe nucleus using Herpes Simplex Virus gene transfer increases anxiety behavior after inescapable stress. J. Neurosci. 22, 4550–4562 (2002).

    Article  CAS  Google Scholar 

  43. Barrot, M. et al. CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Proc. Natl. Acad. Sci. USA 99, 11435–11440 (2002).

    Article  CAS  Google Scholar 

  44. Lucki, I. The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav. Pharmacol. 8, 523–532 (1997).

    Article  CAS  Google Scholar 

  45. Kubicek, S. & Jenuwein, T. A crack in histone lysine methylation. Cell 119, 903–906 (2004).

    Article  CAS  Google Scholar 

  46. Chen, J. et al. Activity-induced expression of common reference genes in individual cns neurons. Lab. Invest. 81, 913–916 (2001).

    Article  CAS  Google Scholar 

  47. Newton, S.S. et al. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J. Neurosci. 23, 10841–10851 (2003).

    Article  CAS  Google Scholar 

  48. Weaver, I.C. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847–854 (2004).

    Article  CAS  Google Scholar 

  49. Clark, S.J., Harrison, J., Paul, C.L. & Frommer, M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res. 22, 2990–2997 (1994).

    Article  CAS  Google Scholar 

  50. Dennis, K. & Levitt, P. Expression of brain derived neurotrophic factor (BDNF) is correlated with dynamic patterns of promoter methylation in the developing mouse forebrain. Brain Res. Mol. Brain Res. 140, 1–9 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Theobald and T. Sasaki for helping with some of the mouse injections; K. Dennis (Vanderbilt University) for supplying the sodium bisulfite protocol for DNA methylation; and G. Petrov for graphic design expertise. This work was supported by grants from the US National Institute of Mental Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric J Nestler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Structure of the Bdnf gene. (PDF 953 kb)

Supplementary Fig. 2

Changes in the H3-K27 di-methylation are specific for the Bdnf P3 and P4 promoters. (PDF 322 kb)

Supplementary Fig. 3

Changes in the H3 hyperacetylation and H3-K4 di-methylation are specific for the Bdnf P3 and P4 promoters. (PDF 451 kb)

Supplementary Fig. 4

H4 acetylation levels at the Bdnf P3 promoter are not changed after chronic defeat stress and imipramine treaments. (PDF 192 kb)

Supplementary Fig. 5 (PDF 3526 kb)

Supplementary Table 1

Locomotor activity in social defeat and control mice. (PDF 59 kb)

Supplementary Table 2

List of all primer sequences used. (PDF 57 kb)

Supplementary Methods (PDF 80 kb)

Supplementary Note (PDF 72 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsankova, N., Berton, O., Renthal, W. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9, 519–525 (2006). https://doi.org/10.1038/nn1659

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1659

This article is cited by

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