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HDAC2 negatively regulates memory formation and synaptic plasticity

Nature volume 459, pages 55–60 (2009)Cite this article

Abstract

Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.

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Figure 1: Mice overexpressing HDAC2, but not HDAC1, show impaired memory formation.
Figure 2: Hdac2 knockout mice show enhanced memory formation.
Figure 3: HDAC2 regulates synapse formation and plasticity in mouse hippocampus.
Figure 4: HDAC2, but not HDAC1, binds to promoters of memory-related genes.
Figure 5: SAHA, an HDAC inhibitor, improves associative learning by targeting HDAC2.

References

  1. West, A. E. et al. Calcium regulation of neuronal gene expression. Proc. Natl Acad. Sci. USA 98, 11024–11031 (2001)

    Article  ADS  CAS  Google Scholar 

  2. 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 

  3. Kurdistani, S. K. & Grunstein, M. Histone acetylation and deacetylation in yeast. Nature Rev. Mol. Cell Biol. 4, 276–284 (2003)

    Article  CAS  Google Scholar 

  4. Goldberg, A. D., Allis, C. D. & Bernstein, E. Epigenetics: a landscape takes shape. Cell 128, 635–638 (2007)

    Article  CAS  Google Scholar 

  5. Alarcon, J. M. et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein–Taybi syndrome and its amelioration. Neuron 42, 947–959 (2004)

    Article  CAS  Google Scholar 

  6. 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 

  7. 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 

  8. 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 

  9. Vecsey, C. G. et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J. Neurosci. 27, 6128–6140 (2007)

    Article  CAS  Google Scholar 

  10. Fischer, A. et al. Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178–182 (2007)

    Article  ADS  CAS  Google Scholar 

  11. Bruserud, O. et al. Histone deacetylase inhibitors in cancer treatment: a review of the clinical toxicity and the modulation of gene expression in cancer cell. Curr. Pharm. Biotechnol. 8, 388–400 (2007)

    Article  CAS  Google Scholar 

  12. Tsankova, N. M. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neurosci. 9, 519–525 (2006)

    Article  CAS  Google Scholar 

  13. Renthal, W. et al. Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli. Neuron 56, 517–529 (2007)

    Article  CAS  Google Scholar 

  14. 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  ADS  CAS  Google Scholar 

  15. Ferrante, R. J. et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J. Neurosci. 23, 9418–9427 (2003)

    Article  CAS  Google Scholar 

  16. Witter, D. J. et al. Optimization of biaryl selective HDAC1&2 inhibitors (SHI-1:2). Bioorg. Med. Chem. Lett. 18, 726–731 (2008)

    Article  CAS  Google Scholar 

  17. Guardiola, A. R. & Yao, T. P. Molecular cloning and characterization of a novel histone deacetylase HDAC10. J. Biol. Chem. 277, 3350–3356 (2002)

    Article  CAS  Google Scholar 

  18. Hubbert, C. et al. HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458 (2002)

    Article  ADS  CAS  Google Scholar 

  19. Salisbury, C. M. & Cravatt, B. F. Activity-based probes for proteomic profiling of histone deacetylase complexes. Proc. Natl Acad. Sci. USA 104, 1171–1176 (2007)

    Article  ADS  CAS  Google Scholar 

  20. Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007)

    Article  ADS  CAS  Google Scholar 

  21. Luikenhuis, S., Giacometti, E., Beard, C. F. & Jaenisch, R. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc. Natl Acad. Sci. USA 101, 6033–6038 (2004)

    Article  ADS  CAS  Google Scholar 

  22. Martin, S. J., Grimwood, P. D. & Morris, R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649–711 (2000)

    Article  CAS  Google Scholar 

  23. Finkbeiner, S. et al. CREB: a major mediator of neuronal neurotrophin responses. Neuron 19, 1031–1047 (1997)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  25. Ballas, N. et al. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121, 645–657 (2005)

    Article  CAS  Google Scholar 

  26. Nott, A. et al. S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons. Nature 455, 411–415 (2008)

    Article  ADS  CAS  Google Scholar 

  27. Hassig, C. A. et al. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl Acad. Sci. USA 95, 3519–3524 (1998)

    Article  ADS  CAS  Google Scholar 

  28. Montgomery, R. L. et al. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev. 21, 1790–1802 (2007)

    Article  CAS  Google Scholar 

  29. Kim, D. et al. Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60, 803–817 (2008)

    Article  CAS  Google Scholar 

  30. Radulovic, J., Ruhmann, A., Liepold, T. & Spiess, J. Modulation of learning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2. J. Neurosci. 19, 5016–5025 (1999)

    Article  CAS  Google Scholar 

  31. Morris, R. G., Garrud, P., Rawlins, J. N. & O’Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982)

    Article  ADS  CAS  Google Scholar 

  32. Breslow, R., Marks, P., Rifkind, R. & Jursic, B. Novel Potent Inducers of Terminal Differentiation and Methods Thereof. US Patent WO/1993/007148 (1993)

    Google Scholar 

  33. Ramon-Molinier, E. Contemporary Research Methods in Neuroanatomy Synaptic Plasticity: Multiple Forms and Mechanisms (Springer, 1970)

    Google Scholar 

  34. Guan, J. S. et al. Interaction with vesicle luminal protachykinin regulates surface expression of δ-opioid receptors and opioid analgesia. Cell 122, 619–631 (2005)

    Article  CAS  Google Scholar 

  35. Hernandez, A. I. et al. Protein kinase Mζ synthesis from a brain mRNA encoding an independent protein kinase Cζ catalytic domain. Implications for the molecular mechanism of memory. J. Biol. Chem. 278, 40305–40316 (2003)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. Scolnick, D. Fass, P. Sklar, T. Petryshen, B. A. Samuels, A. Fischer, C. Frank, D. Kim, S. Su and Y. Hayashi for advice and critical reading of the manuscript; T. Petryshen, A. Graybiel, J. Crittenden and M. C. Lewis for providing the T-maze behaviour model; R. Neve for providing tdTomato HSV. Funding was provided by a grant from the National Institute of Neurological Disorders and Stroke (2 ROI NS051874) to L.-H.T., by a research fund from the Stanley Center for Psychiatric Research to L.-H.T. and S.J.H., by the National Alliance for Research on Schizophrenia and Depression Foundation to S.J.H.; by a fellowship from the Damon-Runyon Cancer Research Foundation and The Dutch Cancer Society (KWF) to J.H.D. R.J. is supported by NIH grants (5-RO1-CA087869, 5-R37-CA084198, 5-RO1-HD0445022); R.A.D. is supported by the Robert A. and Renee E. Belfer Institute for Applied Cancer Science. L.-H.T. is an investigator of the Howard Hughes Medical Institute.

Author Contributions L.-H.T. designed, directed and coordinated the project. J.-S.G. designed and performed the behaviour tests, biochemical assays and morphological analysis in HDACi-treated animals and genetically modified animal models. S.J.H., R.M., J.E.B. contributed to the generation and characterization of HDACis. E.G. generated HDAC1/2OE mice in R.J.’s laboratory. J.-H.D. generated HDAC2KO mice in R.A.D.’s laboratory. N.J., W.X.Y., Y.Z. and E.G. contributed to behavioural tests and biochemical analysis. J.G. performed electrophysiological analysis. T.J.F.N. performed imaging assays for cultured neurons. R.A.D., J.-H.D., E.G. and R.J. critically reviewed the experimental data. The manuscript was written by J.-S.G., S.J.H. and L.-H.T. and was commented on by all the authors.

Author information

Author notes

  1. Jan-Hermen Dannenberg

    Present address: Present address: Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.,

  2. Ji-Song Guan, Stephen J. Haggarty, Emanuela Giacometti and Jan-Hermen Dannenberg: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Brain and Cognitive Sciences,, Picower Institute for Learning and Memory,

    Ji-Song Guan, Nadine Joseph, Jun Gao, Ying Zhou, Xinyu Wang & Li-Huei Tsai

  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA ,

    Ji-Song Guan, Nadine Joseph, Jun Gao, Ying Zhou, Xinyu Wang & Li-Huei Tsai

  3. Stanley Center for Psychiatric Research, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA ,

    Ji-Song Guan, Stephen J. Haggarty, Nadine Joseph, Thomas J. F. Nieland, Ralph Mazitschek, James E. Bradner & Li-Huei Tsai

  4. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA ,

    Stephen J. Haggarty

  5. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA ,

    Emanuela Giacometti & Rudolf Jaenisch

  6. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,

    Emanuela Giacometti & Rudolf Jaenisch

  7. Departments of Medical Oncology, Belfer Institute for Applied Cancer Science, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Jan-Hermen Dannenberg & Ronald A. DePinho

  8. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA,

    Ralph Mazitschek

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Correspondence to Li-Huei Tsai.

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Guan, JS., Haggarty, S., Giacometti, E. et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55–60 (2009). https://doi.org/10.1038/nature07925

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