Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation

被引:288
作者
Gomez-Pinilla, F. [1 ,2 ]
Zhuang, Y. [2 ]
Feng, J. [3 ]
Ying, Z. [1 ]
Fan, G. [3 ]
机构
[1] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90024 USA
[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurosurg, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA
基金
美国国家卫生研究院;
关键词
hippocampus; histone modification; rat; synaptic plasticity; DNA METHYLATION; BDNF TRANSCRIPTION; GENE-TRANSCRIPTION; ENERGY-METABOLISM; MECP2; PHOSPHORYLATION; ANTIDEPRESSANT; DEPRESSION;
D O I
10.1111/j.1460-9568.2010.07508.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
We have evaluated the possibility that the action of voluntary exercise on the regulation of brain-derived neurotrophic factor (BDNF), a molecule important for rat hippocampal learning, could involve mechanisms of epigenetic regulation. We focused the studies on the Bdnf promoter IV, as this region is highly responsive to neuronal activity. We have found that exercise stimulates DNA demethylation in Bdnf promoter IV, and elevates levels of activated methyl-CpG-binding protein 2, as well as BDNF mRNA and protein in the rat hippocampus. Chromatin immunoprecipitation assay showed that exercise increases acetylation of histone H3, and protein assessment showed that exercise elevates the ratio of acetylated : total for histone H3 but had no effects on histone H4 levels. Exercise also reduces levels of the histone deacetylase 5 mRNA and protein implicated in the regulation of the Bdnf gene [N.M. Tsankova et al. (2006) Nat. Neurosci., 9, 519-525], but did not affect histone deacetylase 9. Exercise elevated the phosphorylated forms of calcium/calmodulin-dependent protein kinase II and cAMP response element binding protein, implicated in the pathways by which neural activity influences the epigenetic regulation of gene transcription, i.e. Bdnf. These results showing the influence of exercise on the remodeling of chromatin containing the Bdnf gene emphasize the importance of exercise on the control of gene transcription in the context of brain function and plasticity. Reported information about the impact of a behavior, inherently involved in the daily human routine, on the epigenome opens exciting new directions and therapeutic opportunities in the war against neurological and psychiatric disorders.
引用
收藏
页码:383 / 390
页数:8
相关论文
共 32 条
[1]   MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production [J].
Abuhatzira, Liron ;
Makedonski, Kirill ;
Kaufman, Yotam ;
Razin, Aharon ;
Shemer, Ruth .
EPIGENETICS, 2007, 2 (04) :214-222
[2]   Epigenetic transgenerational actions of endocrine disruptors and mate fertility [J].
Anway, MD ;
Cupp, AS ;
Uzumcu, M ;
Skinner, MK .
SCIENCE, 2005, 308 (5727) :1466-1469
[3]   Depression and Alzheimer's disease: Neurobiological links and common pharmacological targets [J].
Caraci, Filippo ;
Copani, Agata ;
Nicoletti, Ferdinando ;
Drago, Filippo .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2010, 626 (01) :64-71
[4]   Covalent histone modifications underlie the developmental regulation of insulin gene transcription in pancreatic β cells [J].
Chakrabarti, SK ;
Francis, J ;
Ziesmann, SM ;
Garmey, JC ;
Mirmira, RG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (26) :23617-23623
[5]   The yin and yang of MeCP2 phosphorylation [J].
Chao, Hsiao-Tuan ;
Zoghbia, Huda Y. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (12) :4577-4578
[6]   Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2 [J].
Chen, WG ;
Chang, Q ;
Lin, YX ;
Meissner, A ;
West, AE ;
Griffith, EC ;
Jaenisch, R ;
Greenberg, ME .
SCIENCE, 2003, 302 (5646) :885-889
[7]   Exercise affects energy metabolism and neural plasticity-related proteins in the hippocampus as revealed by proteomic analysis [J].
Ding, Qinxue ;
Vaynman, Shoshanna ;
Souda, Puneet ;
Whitelegge, Julian P. ;
Gomez-Pinilla, Fernando .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2006, 24 (05) :1265-1276
[8]   Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice [J].
Duman, Catharine H. ;
Schlesinger, Lee ;
Russell, David S. ;
Duman, Ronald S. .
BRAIN RESEARCH, 2008, 1199 :148-158
[9]   Phenotypic plasticity and the epigenetics of human disease [J].
Feinberg, Andrew P. .
NATURE, 2007, 447 (7143) :433-440
[10]   Epigenetic regulation of neural gene expression and neuronal function [J].
Feng, Jian ;
Fouse, Shaun ;
Fan, Guoping .
PEDIATRIC RESEARCH, 2007, 61 (05) :58R-63R