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The Journal of Neuroscience, June 6, 2007, 27(23):6128-6140; doi:10.1523/JNEUROSCI.0296-07.2007

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Behavioral/Systems/Cognitive
Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation

Christopher G. Vecsey,¹ Joshua D. Hawk,¹ K. Matthew Lattal,⁴ Joel M. Stein,³ Sara A. Fabian,² Michelle A. Attner,² Sara M. Cabrera,⁵ Conor B. McDonough,¹ Paul K. Brindle,⁶ Ted Abel,^1,2,3 and Marcelo A. Wood⁵

¹Neuroscience Graduate Group, ²Department of Biology, and ³Cell and Molecular Biology Graduate Group, University of Pennsylvania 19104, ⁴Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239, ⁵Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, California 92697, and ⁶Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Correspondence should be addressed to either of the following: Marcelo A. Wood, Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697-3800, Email: mwood{at}uci.edu; or Ted Abel, Department of Biology, University of Pennsylvania, 204G Carolyn Lynch Laboratory, Philadelphia, PA 19104, Email: abele{at}sas.upenn.edu

Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance both memory and synaptic plasticity. The current model for the action of HDAC inhibitors assumes that they alter gene expression globally and thus affect memory processes in a nonspecific manner. Here, we show that the enhancement of hippocampus-dependent memory and hippocampal synaptic plasticity by HDAC inhibitors is mediated by the transcription factor cAMP response element-binding protein (CREB) and the recruitment of the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CBP) via the CREB-binding domain of CBP. Furthermore, we show that the HDAC inhibitor trichostatin A does not globally alter gene expression but instead increases the expression of specific genes during memory consolidation. Our results suggest that HDAC inhibitors enhance memory processes by the activation of key genes regulated by the CREB:CBP transcriptional complex.

Key words: histone deacetylase inhibitors; hippocampus-dependent memory; CREB-binding protein; KIX domain; Nr4a1; Nr4a2

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Received Oct. 25, 2005; revised April 26, 2007; accepted April 26, 2007.

Correspondence should be addressed to either of the following: Marcelo A. Wood, Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697-3800, Email: mwood{at}uci.edu; or Ted Abel, Department of Biology, University of Pennsylvania, 204G Carolyn Lynch Laboratory, Philadelphia, PA 19104, Email: abele{at}sas.upenn.edu

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