Epigenetic Regulation of bdnf Gene Transcription in the Consolidation of Fear Memory

被引:597
作者
Lubin, Farah D. [1 ]
Roth, Tania L. [1 ]
Sweatt, J. David [1 ]
机构
[1] Univ Alabama Birmingham, Dept Neurobiol, Evelyn F McKnight Brain Inst, Birmingham, AL 35294 USA
基金
美国国家卫生研究院;
关键词
DNA methylation; histone acetylation; memory; chromatin remodeling; hippocampus; DNA methyltransferase;
D O I
10.1523/JNEUROSCI.1786-08.2008
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 bdnfDNA 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.
引用
收藏
页码:10576 / 10586
页数:11
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