title: Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging.
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 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.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90024, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Miao
authors.initials: M
authors.lastname: Tan
authors.forename: Jun
authors.initials: J
authors.lastname: Kohyama
authors.forename: Marissa
authors.initials: M
authors.lastname: Sneddon
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Watson
authors.forename: Yi E
authors.initials: YE
authors.lastname: Sun
authors.forename: Cui-Wei
authors.initials: CW
authors.lastname: Xie
mesh_terms: D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D057890:Epigenomics / Q000379:methods*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D051548:Histone Acetyltransferases / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D011916:Rats, Inbred F344; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D016622:Silver Staining / Q000379:methods
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D020813:Receptor, trkB; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2