Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging

Yan Zeng, Miao Tan, Jun Kohyama, Marissa Sneddon, Joseph B. Watson, Yi E. Sun, Cui Wei Xie

研究成果: Article

102 引用 (Scopus)

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Aging-related cognitive declines are well documented in humans and animal models. Yet the synaptic and molecular mechanisms responsible for cognitive aging are not well understood. Here we demonstrated age-dependent deficits in long-term synaptic plasticity and loss of dendritic spines in the hippocampus of aged Fisher 344 rats, which were closely associated with reduced histone acetylation, upregulation of histone deacetylase (HDAC)2, and decreased expression of a histone acetyl transferase. Further analysis showed that one of the key genes affected by such changes was the brain-derived neurotrophic factor (Bdnf) gene. Age-dependent reductions in H3 and H4 acetylation were detected within multiple promoter regions of the Bdnf gene, leading to a significant decrease in BDNF expression and impairment of downstream signaling in the aged hippocampus. These synaptic and signaling deficits could be rescued by enhancing BDNF and trkB expression via HDAC inhibition or by directly activating trkB receptors with 7,8-dihydroxyflavone, a newly identified, selective agonist for trkB. Together, our findings suggest that age-dependent declines in chromatin histone acetylation and the resulting changes in BDNF expression and signaling are key mechanisms underlying the deterioration of synaptic function and structure in the aging brain. Furthermore, epigenetic or pharmacological enhancement of BDNF-trkB signaling could be a promising strategy for reversing cognitive aging.

元の言語English
ページ(範囲)17800-17810
ページ数11
ジャーナルJournal of Neuroscience
31
発行部数49
DOI
出版物ステータスPublished - 2011 12 7
外部発表Yes

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ASJC Scopus subject areas

  • Neuroscience(all)

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