While multiple epigenetic changes are known to accompany the weakening and strengthening of synaptic connections—and hence participate in the formation of memories—these molecular-level events are still poorly understood. Taking a close look at these changes, scientists based at the German Center for Neurodegenerative Diseases (DZNE) discerned that neuroplasticity depends on patterns of DNA methylation, as expected, but also uncovered a couple of surprises.
The DZNE scientists, led by Stefan Bonn, Ph.D., and André Fischer, Ph.D., stimulated long-term memory in mice, by training the animals to recognize a specific test environment. Based on tissue samples, the researchers were able to discern to what extent this learning task triggered changes in the activity of the genes in the mice's brain cells.
The scientists found that the epigenetic modifications accompanying memory and learning were accompanied by both histone changes as well as DNA methylation changes. However, histone modifications had little effect on the activity of genes involved in neuroplasticity. In addition, the scientists discovered epigenetic modifications not only in nerve cells, but also in non-neuronal cells of the brain.
These findings appeared December 14 in the journal Nature Neuroscience, in an article entitled, “DNA methylation changes in plasticity genes accompany the formation and maintenance of memory.” This article detailed how the DZNE scientists and their colleagues examined chromatin modification changes in two distinct mouse brain regions, two cell types, and three time points before and after contextual learning.
“We found that histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression,” the article’s authors wrote. “Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning.”
The authors concluded that their work added to existing evidence for a molecular framework of memory acquisition and maintenance, a framework in which DNA methylation alters the expression and splicing of genes involved in functional plasticity and neuronal wiring. In addition, the leaders of the current study commented on the weight their findings give to DNA methylation, as well as the potential role of non-neuronal epigenetic changes.
Our observations suggest that neuroplasticity is to a large extent regulated by DNA methylation,” said Prof. Dr. Fischer, site speaker for the DZNE in Göttingen and professor at the University Medical Center Göttingen (UMG). “Although this is not a new hypothesis, our study provides an unprecedented amount of supporting evidence. Thus, methylation may indeed be an important molecular constituent of long-term memory.”
“The relevance of non-neuronal cells for memory,” he added, “is an interesting topic that we will continue to pursue.”
As for the current study’s practical implications, Magali Hennion, Ph.D., a staff member in Dr. Bonn’s group, offered the following: “Research on epigenetic changes that are related to memory processes is still at an early stage. We look at such features, not only for the purpose of a better understanding of how memory works. We also look for potential targets for drugs that may counteract memory decline. Ultimately, our research is about therapies against Alzheimer's and similar brain diseases.”
“Methylation,” emphasized Prof. Fisher, “could be a sort of code for memory content and a potential target for therapies against Alzheimer's disease.”