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The Journal of Neuroscience, October 15, 2008, 28(42):10576-10586; doi:10.1523/JNEUROSCI.1786-08.2008

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Cellular/Molecular
Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Fear Memory

Farah D. Lubin, Tania L. Roth, and J. David Sweatt

Department of Neurobiology, The Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294

Correspondence should be addressed to either of the following: Farah D. Lubin or J. David Sweatt, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294. Email: flubin{at}nrc.uab.edu or Email: dsweatt{at}nrc.uab.edu

Long-term memory formation requires selective changes in gene expression. Here, we determined the contribution of chromatin remodeling to learning-induced changes in brain-derived neurotrophic factor (bdnf) gene expression in the adult hippocampus. Contextual fear learning induced differential regulation of exon-specific bdnf mRNAs (I, IV, VI, IX) that was associated with changes in bdnf DNA methylation and altered local chromatin structure. Infusions of zebularine (a DNA methyltransferase inhibitor) significantly altered bdnf DNA methylation and triggered changes in exon-specific bdnf mRNA levels, indicating that altered DNA methylation is sufficient to drive differential bdnf transcript regulation in the hippocampus. In addition, NMDA receptor blockade prevented memory-associated alterations in bdnf DNA methylation, resulting in a block of altered bdnf gene expression in hippocampus and a deficit in memory formation. These results suggest epigenetic modification of the bdnf gene as a mechanism for isoform-specific gene readout during memory consolidation.

Key words: DNA methylation; histone acetylation; memory; chromatin remodeling; hippocampus; DNA methyltransferase

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Received April 23, 2008; revised Aug. 14, 2008; accepted Sept. 5, 2008.

Correspondence should be addressed to either of the following: Farah D. Lubin or J. David Sweatt, Department of Neurobiology, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham, AL 35294. Email: flubin{at}nrc.uab.edu or Email: dsweatt{at}nrc.uab.edu

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