Abstract
Cognitive abilities, particularly memory formation, vary substantially in the elderly, with some individuals exhibiting dramatic decline with age while others maintain function well into late life. Epigenetic modifications suggest an intriguing mechanism to account for the range of cognitive outcomes in aging as they are responsive to environmental influences and affect gene transcription in cognitively relevant brain regions. Leveraging a well-characterized rat model of neurocognitive aging that recapitulates the range of outcomes seen in humans, we previously identified gene expression profiles in the CA3 subregion of the hippocampus that distinguish between young and aged subjects as well as between impaired and preserved spatial memory function. To investigate the influence of epigenetics on these profiles, we examined genomic CpG DNA methylation in the promoter regions of three neurophysiologically relevant genes (Gabra5, Hspa5 and Syn1) whose expression levels decrease with age and correlate with spatial memory performance. Consistent with mRNA decreases, DNA methylation increased in aged rats relative to young in CpG dense regions of all target promoters examined. However, no correlation with cognition was found. Focused analysis of the Gabra5 gene found that methylation changes were limited to the CpG island and varied substantially across individual CpGs. Methylation at one CpG correlated with learning and demonstrated a significant difference between memory impaired aged rats and those with intact learning. These data provide evidence that broad age-dependent DNA methylation changes occur in CpG dense promoter regions of cognitively relevant genes but suggest that methylation at single CpGs may be more pertinent to individual cognitive differences.