Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner

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.

Transgenerational Effects of Arsenic Exposure on Learning and Memory in Rats: Crosstalk between Arsenic Methylation, Hippocampal Metabolism, and Histone Modifications

“…To support our findings, it was previously reported that the enhanced H3K4me2 in the Bdnf promoter of the lateral-medial hypothalamic forebrain bundle leads to Bdnf overexpression . Ionescu-Tucker et al also found that the reduced H3K9me3 in the brain is one of the reasons for BDNF activation . Therefore, we propose that arsenic exposure impaired learning and memory ability by inhibiting key gene expressions, which were attributable to the repressed H3K4 methylation and acetylation and the enhanced H3K9 methylation in rat hippocampus.…”

“…39 Ionescu-Tucker et al also found that the reduced H3K9me3 in the brain is one of the reasons for BDNF activation. 40 Therefore, we propose that arsenic exposure impaired learning and memory ability by inhibiting key gene expressions, which were attributable to the repressed H3K4 methylation and acetylation and the enhanced H3K9 methylation in rat hippocampus.…”

Myristic acid alleviates hippocampal aging correlated with GABAergic signaling

“…KEGG pathway analysis was found that GABRB2 was upregulated whereas GABRA2 was downregulated, which was verified by IHC of hippocampus between young and aging mice. Previous studies also demonstrated that GABRA2 expression decreased with age in the hippocampus ( 9 , 10 ). However, aging-related disorders on GABRB2 expression are contradictory.…”

“…Generally, GABA exerts its effects on nerves mainly through its receptors; GABRA2 (GABAA receptor subunit alpha2) and GABRB2 (GABAA receptor subunit beta2) are the two important subunits of GABAA receptor, respectively. Previous studies demonstrated that GABRA2 expression decreased with age in the hippocampus ( 9 , 10 ). However, aging-related disorders on GABRB2 expression are contradictory and need further experimental validation.…”

What Muscle Signals Mediate the Beneficial Effects of Exercise on Cognition?

“…81 For example, exercise decreased the repressive histone modification H3K9me3 at a BDNF promoter, leading to an increase in BDNF in aged mice. 82…”