Epigenetic Regulation ofbdnfGene Transcription in the Consolidation of Fear Memory

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Abstract
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-specificbdnfmRNAs (I, IV, VI, IX) that was associated with changes inbdnfDNA methylation and altered local chromatin structure. Infusions of zebularine (a DNA methyltransferase inhibitor) significantly alteredbdnfDNA methylation and triggered changes in exon-specificbdnfmRNA levels, indicating that altered DNA methylation is sufficient to drive differentialbdnftranscript regulation in the hippocampus. In addition, NMDA receptor blockade prevented memory-associated alterations inbdnfDNA methylation, resulting in a block of alteredbdnfgene expression in hippocampus and a deficit in memory formation. These results suggest epigenetic modification of thebdnfgene as a mechanism for isoform-specific gene readout during memory consolidation.