SALT LAKE CITY—The concept of epigenetics is central to the progress that has been made recently toward understanding the mechanisms of memory retention. The term epigenetics is commonly used to capture the influences on gene expression made by structural changes in chromatin, which is the complex combination of DNA, RNA, and protein of which chromosomes are composed. Epigenetic processes are not encoded in the DNA but can be critical to fundamental cell processes. Like the epigenetic changes that permit cells to retain heritable traits not in the genetic code, changes in the chromatin structure in specific neurons appear to be the foundation of memory retention.

“One of the key roles of epigenetics is perpetuation of cellular genotypes. For memory formation, epigenetic mechanisms have been co-opted in the cortex for long-term memory storage,” explained J. David Sweatt, PhD, Professor and Chairman, Department of Neurobiology, University of Alabama, Birmingham. Speaking at the 133rd Annual Meeting of the American Neurological Association, Dr. Sweatt indicated that the understanding of the mechanisms that control memory formation is still at a relatively early stage, but “experiments imply there is a chemical modification occurring when you are making a memory that permits sustained storage.”

Memory Storage—An Epigenetic Phenomenon
In neurons responsible for memory, the evidence that this process can be traced to changes in chromatin structure is now being supported in animal models, but the concept of epigenetics is fundamental to recent progress. The chemical processes that produce changes in the three-dimensional chromatin structure appear to be important for storage of a variety of critical information about protein-mediated functions specific to that cell type. For example, the ability of a hepatocyte to remain a hepatocyte and pass on its function to its progeny is now understood to be an epigenetic phenomenon. The DNA of the hepatocyte is the same as that of the neuron, but epigenetic chemical processes control how the information is expressed.

The general model of epigenetic cell memory involves chemical changes to histones, which are basic proteins in cell nuclei that participate in gene regulation. Acetylation of histones with histone acetyltransferases is generally an activating function. Methylation of histones, like methylation of DNA, is a deactivating or silencing function. These general concepts appear to be relevant to understanding cell memory even in plant cells, but there is increasing evidence that a comparable process governs neurologic memory in animals.

Chemical Foundations of Memory
In animals, fear conditioning has been associated with acetylation of histone H3. When exposed to a noxious stimulus, this acetylation appears to be a fundamental step for allowing recall of the experience when reexposed. Animal models with deficient acetylation demonstrate impairment in memory formation and are less likely to show fear upon reexposure. However, acetylation of H3 is important but may not be sufficient for memory retention. Methylation of cytosines in DNA appears to also play an important role in consolidating or preserving the information. Blocking DNA methylation, like blocking initial histone acetylation, appears to adversely influence an animal’s ability to remember a noxious stimulus when evaluated 24 hours later.

“Mice freeze when they are in a threatening environment, and we have used this characteristic to gauge their mental status,” reported Dr. Sweatt in explaining one of the methods of performing controlled experiments for memory loss and retention. “By manipulating methyltransferase [a key enzyme involved in methylation], we can attenuate long-term memory formation.”

It has been theorized that methylation is an irreversible process, at least as it involves cell DNA gene expression, which would complicate application of this model to understanding memory loss. However, there is recent evidence that demethylation is feasible and does lead to reversal of long-term memory formation. Relative to controls, the freezing activity in mice can be greatly diminished when the animals are reexposed to a noxious stimulus after being given an inhibitor of methylation. Chemical modifications consistent with methylation can also be detected with polymerase chain reaction, supporting the concept that memory formation is associated with specific chemical changes.

Extending the Concept
The animal studies have been largely conducted in the hippocampus where memory storage is relatively transient. Longer-term memories are stored in the cortex, but it is strongly suspected that the basic processes are the same. Indeed, the basic concepts of memory appear to be consistent for the type of memory required by cells to fulfill functions dependent on posttranscriptional protein activity and the type of memory within the CNS that animals use to modify their response to the environment.

“If you remember anything today, it will be in part because of changes in the three-dimensional conformation of the chromatin in your CNS,” Dr. Sweatt said. From the practical standpoint, pharmacologic therapies affecting histone acetylation and methylation are now being developed for the purpose of treating diseases that involve memory loss, such as Alzheimer’s disease. Although it is unclear how far away such treatments may be, progress in outlining the chemical foundations of memory formation provides encouragement.

—Theodore Bosworth

Memory Retention Is Traced to Epigenetic Regulation of Gene Expression