TY - JOUR
T1 - HDAC2 negatively regulates memory formation and synaptic plasticity
AU - Guan, Ji Song
AU - Haggarty, Stephen J.
AU - Giacometti, Emanuela
AU - Dannenberg, Jan Hermen
AU - Joseph, Nadine
AU - Gao, Jun
AU - Nieland, Thomas J.F.
AU - Zhou, Ying
AU - Wang, Xinyu
AU - Mazitschek, Ralph
AU - Bradner, James E.
AU - DePinho, Ronald A.
AU - Jaenisch, Rudolf
AU - Tsai, Li Huei
N1 - Funding Information:
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.
PY - 2009/5/7
Y1 - 2009/5/7
N2 - 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.
AB - 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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U2 - 10.1038/nature07925
DO - 10.1038/nature07925
M3 - Article
C2 - 19424149
AN - SCOPUS:65549123471
SN - 0028-0836
VL - 459
SP - 55
EP - 60
JO - Nature
JF - Nature
IS - 7243
ER -