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

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)17800-17810
Number of pages11
JournalJournal of Neuroscience
Volume31
Issue number49
DOIs
Publication statusPublished - 2011 Dec 7
Externally publishedYes

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Neuronal Plasticity
Brain-Derived Neurotrophic Factor
Epigenomics
Acetylation
Histones
Hippocampus
Histone Deacetylase 2
trkB Receptor
Genes
Dendritic Spines
Histone Deacetylases
Transferases
Genetic Promoter Regions
Chromatin
Up-Regulation
Animal Models
Pharmacology
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging. / Zeng, Yan; Tan, Miao; Kohyama, Jun; Sneddon, Marissa; Watson, Joseph B.; Sun, Yi E.; Xie, Cui Wei.

In: Journal of Neuroscience, Vol. 31, No. 49, 07.12.2011, p. 17800-17810.

Research output: Contribution to journalArticle

Zeng, Yan ; Tan, Miao ; Kohyama, Jun ; Sneddon, Marissa ; Watson, Joseph B. ; Sun, Yi E. ; Xie, Cui Wei. / Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 49. pp. 17800-17810.
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