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HDAC2 negatively regulates memory formation and synaptic plasticity

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  • Ji-Song Guan

    (Picower Institute for Learning and Memory
    Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Stanley Center for Psychiatric Research, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA)

  • Stephen J. Haggarty

    (Stanley Center for Psychiatric Research, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
    Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02142, USA)

  • Emanuela Giacometti

    (Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
    Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA)

  • Jan-Hermen Dannenberg

    (Belfer Institute for Applied Cancer Science, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
    Present address: Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.)

  • Nadine Joseph

    (Picower Institute for Learning and Memory
    Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Stanley Center for Psychiatric Research, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA)

  • Jun Gao

    (Picower Institute for Learning and Memory
    Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA)

  • Thomas J. F. Nieland

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

  • Ying Zhou

    (Picower Institute for Learning and Memory
    Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA)

  • Xinyu Wang

    (Picower Institute for Learning and Memory
    Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA)

  • Ralph Mazitschek

    (Stanley Center for Psychiatric Research, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
    Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • James E. Bradner

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

  • Ronald A. DePinho

    (Belfer Institute for Applied Cancer Science, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Rudolf Jaenisch

    (Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
    Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA)

  • Li-Huei Tsai

    (Picower Institute for Learning and Memory
    Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
    Stanley Center for Psychiatric Research, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA)

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.

Suggested Citation

  • Ji-Song Guan & Stephen J. Haggarty & Emanuela Giacometti & Jan-Hermen Dannenberg & Nadine Joseph & Jun Gao & Thomas J. F. Nieland & Ying Zhou & Xinyu Wang & Ralph Mazitschek & James E. Bradner & Ronal, 2009. "HDAC2 negatively regulates memory formation and synaptic plasticity," Nature, Nature, vol. 459(7243), pages 55-60, May.
    • Handle: RePEc:nat:nature:v:459:y:2009:i:7243:d:10.1038_nature07925
    DOI: 10.1038/nature07925
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    Cited by:

    1. Tharick A. Pascoal & Mira Chamoun & Elad Lax & Hsiao-Ying Wey & Monica Shin & Kok Pin Ng & Min Su Kang & Sulantha Mathotaarachchi & Andrea L. Benedet & Joseph Therriault & Firoza Z. Lussier & Frederic, 2022. "[11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Ravinder K. Bahia & Xiaoguang Hao & Rozina Hassam & Orsolya Cseh & Danielle A. Bozek & H. Artee Luchman & Samuel Weiss, 2023. "Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Tian Wang & Jie Zhang & Yi Xu, 2020. "Epigenetic Basis of Lead-Induced Neurological Disorders," IJERPH, MDPI, vol. 17(13), pages 1-23, July.
    4. Jamal B. Williams & Qing Cao & Wei Wang & Young-Ho Lee & Luye Qin & Ping Zhong & Yong Ren & Kaijie Ma & Zhen Yan, 2023. "Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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