RT Journal Article
SR Electronic
T1 Epigenetic Enhancement of BDNF Signaling Rescues Synaptic Plasticity in Aging
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 17800
OP 17810
DO 10.1523/JNEUROSCI.3878-11.2011
VO 31
IS 49
A1 Yan Zeng
A1 Miao Tan
A1 Jun Kohyama
A1 Marissa Sneddon
A1 Joseph B. Watson
A1 Yi E. Sun
A1 Cui-Wei Xie
YR 2011
UL http://www.jneurosci.org/content/31/49/17800.abstract
AB 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 acetyltransferase. 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.