Epigenetic Regulation ofBDNFGene in Response to Stress

Abstract

Neuronal plasticity induced by changes in synaptic morphology and function is well known to play a pivotal role in leaning and memory as well as adaptation to stress. It is suggested that these plastic changes are due to orchestration of alterations in gene expression in the brain. Recent advances in molecular biology have provided evidence that epigenetic mechanisms, such as DNA methylation and histone modification, are crucial to gene transcription in the mammalian brain. Our research group has recently investigated the involvement of histone actylation at the promoter of the brain-derived neurotrophic factor (BDNF) gene in stress-induced reduction in BDNF, as well as in fear conditioning-induced enhancement of BDNF, in the rat hippocampus. The results of the stress study demonstrated that single-immobilization stress significantly reduced the levels of total, exon I, and exon IV BDNF mRNA, and also significantly reduced acetylation levels of histone H3, but not H4, at the promoter of exons I, IV, and VI. The results of the fear conditioning study showed that footshock stress significantly increased the levels of total, exon I, and exon IV BDNF mRNA, with significantly increased acetylation levels of both histone H3 and H4, at the promoter of exons I and IV, followed by enhanced freezing to fear-context exposure. These findings suggest that changes in BDNF transcription in the rat hippocampus in response to stressful stimuli are, at least in part, regulated by histone acetylation status.

17β-Estradiol regulates histone alterations associated with memory consolidation and increases Bdnf promoter acetylation in middle-aged female mice

“…Collectively, this literature led us to hypothesize that E 2 would increase histone H3 acetylation at Bdnf promoters. We focused on the Bdnf pI, pII, and pIV promoters because H3 acetylation of these promoters is closely associated with hippocampal learning and aging (Lubin et al 2008;Fuchikami et al 2010;Perovic et al 2013). We found that aging significantly decreased H3 acetylation of pI and pIV, and tended to decrease acetylation of pII.…”

“…Of these promoters, pI, pII, pIV, and pVI are the most common in the brain (Baj et al 2011). In the hippocampus, memory consolidation is associated with increased histone H3 acetylation at the pIV promoter (Lubin et al 2008), and fear conditioning increases H3 acetylation at pI and pIV (Fuchikami et al 2010). In contrast, aging is associated with a decrease in pII and pIV BDNF mRNA in the hippocampus of male rats (Perovic et al 2013), but changes in acetylation have not been examined.…”

Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease

“…Therefore, it is reasonable to deduce that the increased hyperacetylation we observe in cultured neurons in this study is either not substantially contributing to Bdnf promoter regulation or that some other repressive protein(s) upregulated by increased histone acetylation may be acting to diminish Bdnf mRNA levels. While we only measured global H3 and H4 N-terminal acetylation at basal levels, others have reported that with memory formation, increased histone acetylation causes a corresponding in vivo increase in Bdnf transcript levels (Bredy et al 2007;Fuchikami et al 2010). It will be interesting to determine whether the age and AD-related H3 and H4 hyperacetylation of hippocampal/cortical neurons change with memory formation in aged mice and in an Alzheimer mouse model.…”

“…For example, fear conditioning with extinction not only increases Bdnf I and IV transcript variants in the mouse prefrontal cortex but also decreases lysine acetylation of H3 and increases acetylation of H4 at the promoters of Bdnf I and IV, respectively (Bredy et al 2007). Also, fear conditioning in post traumatic stress disorder model animals causes an increase in Bdnf I, IV and IXa variants as well as increased acetylation of H3 and H4 at the promoters of Bdnf I and IV in the rat hippocampus (Fuchikami et al 2010). Because memory is greatly affected in AD, the role of Bdnf in AD has been widely examined (Caccamo et al 2010;Connor et al 1997;Peng et al 2009).…”

The potential of epigenetics in stress-enhanced fear learning models of PTSD

“…Using a 2 h restraint stress paradigm, Fuchikami et al reported lower histone H3 acetylation of Bdnf in the hippocampus, accompanied by corresponding decreases in Bdnf mRNA expression (Fuchikami et al 2010). However, this effect was not reproduced in a more recent study (Ieraci et al 2015).…”