Abstract
Exercise improves cognition in the aging brain and is a key regulator of neuronal plasticity genes such as BDNF. However, the mechanism by which exercise modifies gene expression continues to be explored. The repressive histone modification H3K9me3 has been shown to impair cognition, reduce synaptic density and decrease BDNF in aged but not young mice. Treatment with ETP69, a selective inhibitor of H3K9me3’s catalyzing enzyme (SUV39H1), restores synapses, BDNF and cognitive performance. GABA receptor expression, which modulates BDNF secretion, is also modulated by exercise and H3K9me3. In this study, we examined if exercise and ETP69 regulated neuronal plasticity genes by reducing H3K9me3 at their promoter regions. We further determined the effect of age on H3K9me3 promoter binding and neuronal plasticity gene expression. Exercise and ETP69 decreased H3K9me3 at BDNF promoter VI in aged mice, corresponding with an increase in BDNF VI expression with ETP69. Exercise increased GABRA2 in aged mice while increasing BDNF 1 in young mice, and both exercise and ETP69 reduced GABRA2 in young mice. Overall, H3K9me3 repression at BDNF and GABA receptor promoters decreased with age. Our findings suggest that exercise and SUV39H1 inhibition differentially modulate BDNF and GABRA2 expression in an age dependent manner.
Highlights
Exercise has been shown to improve cognition in the aged brain across a range of clinical and animal studies (van Praag et al, 2005; Kirk-Sanchez and McGough, 2014; Snigdha et al, 2014)
We first investigated if ETP69 and exercise affected H3K9 trimethylation levels at brain derived neurotrophic factor (BDNF) promoter regions
We examined BDNF I, IV, and VI as these regulatory exons are highly expressed in the hippocampus (Aid et al, 2007)
Summary
Exercise has been shown to improve cognition in the aged brain across a range of clinical and animal studies (van Praag et al, 2005; Kirk-Sanchez and McGough, 2014; Snigdha et al, 2014) Underlying these improvements are changes to the expression of genes related to neuronal plasticity. ETP69 treatment before or after acquisition of an OLM task increased total BDNF levels and decreased H3K9me at the BDNF 1 promoter (Snigdha et al, 2016). These findings demonstrate that H3K9me leads to memory decline, reduces synaptic plasticity, and represses BDNF expression in aged mice. Further research is needed to determine if exercise-induced increases in neuronal gene expression correlate with a reduction in H3K9me at promoter regions
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