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J. Biol. Chem., Vol. 281, Issue 23, 15763-15773, June 9, 2006

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Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus^*

From the Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030

DNA (cytosine-5) methylation represents one of the most widely used mechanisms of enduring cellular memory. Stable patterns of DNA methylation are established during development, resulting in creation of persisting cellular phenotypes. There is growing evidence that the nervous system has co-opted a number of cellular mechanisms used during development to subserve the formation of long term memory. In this study, we examined the role DNA (cytosine-5) methyltransferase (DNMT) activity might play in regulating the induction of synaptic plasticity. We found that the DNA within promoters for reelin and brain-derived neurotrophic factor, genes implicated in the induction of synaptic plasticity in the adult hippocampus, exhibited rapid and dramatic changes in cytosine methylation when DNMT activity was inhibited. Moreover, zebularine and 5-aza-2-deoxycytidine, inhibitors of DNMT activity, blocked the induction of long term potentiation at Schaffer collateral synapses. Activation of protein kinase C in the hippocampus decreased reelin promoter methylation and increased DNMT3A gene expression. Interestingly, DNMT activity is required for protein kinase C-induced increases in histone H3 acetylation. Considered together, these results suggest that DNMT activity is dynamically regulated in the adult nervous system and that DNMT may play a role in regulating the induction of synaptic plasticity in the mature CNS.

Received for publication, November 11, 2005 , and in revised form, March 20, 2006.

^* This work was supported by National Institutes of Health Grant MH57014 (to J. D. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Dept. of Pharmacology and the Waisman Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706.

² Present address: Dept. of Neurobiology, University of Alabama Birmingham, Birmingham, AL 35294.

³ Present address: Center for Learning and Memory, University of Texas, Austin, TX 78712.

⁴ To whom correspondence should be addressed: Dept. of Neurobiology, University of Alabama Birmingham, SHEL 1010, 1530 3rd Ave. S., Birmingham, AL 35294-2182. Tel.: 205-975-5196; Fax: 205-975-7394; E-mail: dsweatt{at}nrc.uab.edu.

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