Increased DNA methylation of Igf2 in the male hippocampus regulates age-related deficits in synaptic plasticity and memory

The aging process is characterized by a general decline in cognitive abilities, which affects nearly 33 % of U.S. adults over the age of 70 and is a risk factor for the development of dementia and Alzheimer's disease. Numerous studies have reported increased neuroinflammation and impaired synaptic plasticity and memory with age in the hippocampus, a major brain region involved in the formation and storage of most memories. However, much remains unknown about the mechanisms that contribute to age-related deficits in synaptic plasticity and memory. The Insulin-like growth factor 2 (Igf2) is a genomic imprinted gene that is expressed from a single allele in all species. Though IGF2 has been shown to be important in development, synaptic plasticity, and memory formation in the hippocampus and administration of IGF2 can improve memory late in life, whether changes in regulation of this gene contribute to age-related memory decline have yet to be explored. Here, we show that aged (24 months) male rats have increased CpG-site specific promoter methylation and reduced expression of Igf2 in the hippocampus relative to young adult (3 months) and middle-aged (12 months) rats. Importantly, CRISPR-dCas9 mediated increase of DNA 5-hydroxymethylation, an active transcriptional mark, of the Igf2 promoter in the hippocampus improved memory and long-term potentiation in aged, but not middle-aged, rats. These data indicate that increased DNA methylation of Igf2 in the hippocampus contributes to age-related deficits in synaptic plasticity and memory.