HDAC2 negatively regulates memory formation and synaptic plasticity

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, Ronald A. DePinho, Rudolf Jaenisch and Li-Huei Tsai ()
Additional contact information
Ji-Song Guan: Picower Institute for Learning and Memory
Stephen J. Haggarty: Stanley Center for Psychiatric Research, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
Emanuela Giacometti: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
Jan-Hermen Dannenberg: Belfer Institute for Applied Cancer Science, Medicine and Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Nadine Joseph: Picower Institute for Learning and Memory
Jun Gao: Picower Institute for Learning and Memory
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
Xinyu Wang: Picower Institute for Learning and Memory
Ralph Mazitschek: Stanley Center for Psychiatric Research, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, 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
Li-Huei Tsai: Picower Institute for Learning and Memory

Nature, 2009, vol. 459, issue 7243, 55-60

Abstract: 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.

Date: 2009
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DOI: 10.1038/nature07925

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