The Epigenetics Revolution

The cortex is like a hard drive on a computer with gigabytes of storage. The hippocampus is more like the RAM (random access memory) chip, where data are temporarily processed before being deleted, or transferred to the hard drive for permanent storage. Our brain separates out different functions to selected cell populations in different anatomical regions. This is why memory loss is rarely all-encompassing. Depending on the clinical condition, for example, either one of short-term or long-term memory may be relatively lost or remain relatively intact. It makes a lot of sense for these different functions to be separated in our brains. Just try to imagine life if we remembered everything that ever happened – the phone number that we dialled only once, every word a dull stranger said to us on a train, or the canteen menu from a wet Wednesday three years ago.

The complexity of our memory systems is one of the reasons why it is quite a difficult area to study, because it can be difficult to set up experiments where we are absolutely sure which aspects of memory our experimental techniques are actually addressing. But one thing we know for sure is that memory involves long-term changes in gene expression, and in the way neurons make connections with one another. And that again leads to the hypothesis that epigenetic mechanisms may play a role.

In mammals, both DNA methylation and histone modifications play a role in memory and learning. Rodent studies have shown that these changes may be targeted to very specific genes in discrete regions of the brain, as we have come to expect. For example, the DNA methyltransferase proteins DNMT3A and DNMT3B increase in expression in the adult rat hippocampus in a particular learning and memory model. Conversely, treating these rats with a DNA methyltransferase inhibitor such as 5-azacytidine blocks memory formation and affects both the hippocampus and the cortex[225].

A particular histone acetyltransferase (protein which adds acetyl groups to histones) gene is mutated in a human disorder called Rubinstein-Taybi syndrome. Mental retardation is a frequent symptom in this disease. Mice with a mutant version of this gene also have low levels of histone acetylation in the hippocampus, as we would predict. They also have major problems in long-term memory processing in the hippocampus[226]. When these mice were treated with SAHA, the histone deacetylase inhibitor, acetylation levels in the hippocampus went up, and the memory problems improved[227].

SAHA can inhibit many different histone deacetylases, but in the brain some of its targets seem to be more important than others. The two most highly expressed enzymes of this class are HDAC1 and HDAC2. These differ in the ways they are expressed in the brain. HDAC1 is predominantly expressed in neural stem cells, and in a supportive, protective population of non-neurons called glial cells. HDAC2 is predominantly expressed in neuronal cells[228], so it’s unsurprising that this is the histone deacetylase that is most important in learning and memory.

Mice whose neurons over-express Hdac2 have poor long-term memory, even though their short-term memory is fine. Mice whose neurons don’t express any Hdac2 have excellent memories. These data show us that Hdac2 has a negative effect on memory storage. The neurons which over-expressed Hdac2 formed far fewer connections than normal, whereas the opposite was true for the neurons lacking Hdac2. This supports our model of epigenetically-driven changes in gene expression ultimately altering complex networks in the brain. SAHA improves memory in the mice that over-express Hdac2, presumably by dampening down its effects on histone acetylation and gene expression. SAHA also improves memory in normal mice[229].

In fact, increased acetylation levels in the brain seem to be consistently associated with improved memory. Learning and memory both improved in mice kept in conditions known as environmentally enriched. This is a fancy way of saying they had access to two running wheels and the inside of a toilet roll. The histone acetylation levels in the hippocampus and cortex were increased in the mice in the more entertaining surroundings. Even in these mice, the histone acetylation levels and memory skills improved yet further if they were treated with SAHA[230].

We can see a consistent trend emerging. In various different model systems, learning and memory improve when animals are treated with DNA methyltransferase inhibitors, and especially with histone deacetylase inhibitors. As we saw in the last chapter, there are drugs licensed in both these classes, such as 5-azacytidine and SAHA, respectively. It’s very tempting to speculate about taking these anti-cancer drugs and using them in conditions where memory loss is a major clinical problem, such as Alzheimer’s disease. Perhaps we might even use them as general memory enhancers in the wider population.