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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.

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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.

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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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