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The Journal of Neuroscience, November 14, 2007, 27(46):12732-12742; doi:10.1523/JNEUROSCI.2522-07.2007

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Cellular/Molecular
The Nuclear Kinase Mitogen- and Stress-Activated Protein Kinase 1 Regulates Hippocampal Chromatin Remodeling in Memory Formation

Wilson B. Chwang,¹ J. Simon Arthur,³ Armin Schumacher,² and J. David Sweatt^1,4

Departments of ¹Neuroscience and ²Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, ³Medical Research Council Protein Phosphorylation Unit, Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom, and ⁴Department of Neurobiology and the Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294

Correspondence should be addressed to J. David Sweatt at the above address. Email: dsweatt{at}nrc.uab.edu

The extracellular signal-regulated kinase (ERK)/MAPK (mitogen-activated protein kinase) cascade has been established as a potent regulator of gene transcription in long-term memory formation, but the precise mechanisms of this regulation are poorly understood. ERK does not directly affect many of its nuclear targets, but rather must act through intermediary kinases. In this study, we investigated the role of mitogen- and stress-activated protein kinase 1 (MSK1), a nuclear kinase downstream of ERK, in chromatin remodeling during hippocampus-dependent memory formation. Mice lacking MSK1 show impaired Pavlovian fear conditioning and spatial learning, as well as a deficiency in histone phosphorylation and acetylation in the hippocampus after fear training. In addition, hippocampal slices from MSK1 knock-out mice exhibit a deficiency in both histone phosphorylation and acetylation after activation of the ERK pathway in vitro. In vivo injections of a histone deacetylase inhibitor, sodium butyrate, fail to alleviate the fear conditioning deficit in MSK1 knock-out mice. Finally, MSK1 knock-out mice demonstrate a deficiency in cAMP response element-binding protein (CREB) phosphorylation after fear training, which persists after sodium butyrate injection. This suggests that CREB phosphorylation and histone acetylation represent parallel targets of MSK1 function. Our study identifies MSK1 as an important regulator of chromatin remodeling in long-term memory.

Key words: epigenetics; memory; histones; MAPK; MSK1; transcription

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Received June 4, 2007; revised Sept. 17, 2007; accepted Oct. 8, 2007.

Correspondence should be addressed to J. David Sweatt at the above address. Email: dsweatt{at}nrc.uab.edu

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