The Epigenetics Revolution

One of the tests used to investigate how depressed the mice become in response to stress is called the sucrose-preference test. Normal happy mice love sugared water, but when they are depressed they aren’t so interested in it. This decreased response to a pleasant stimulus is called anhedonia. It seems to be one of the best surrogate markers in animals for human depression[218]. Most people who have been severely depressed talk about losing interest in all the things that used to make life joyful before they became ill. When the stressed mice were treated with SSRI anti-depressants, their interest in the sugared water gradually increased. But when they were treated with SAHA, the HDAC inhibitor, they regained their interest in their favourite drink much faster[219].

It’s not just in the jumpy or chilled mice that histone deacetylase inhibitors can change animal behaviour. It’s also relevant to the baby rats who don’t get much maternal licking and grooming. These are the ones that normally grow up to be chronically stressed, with over-activation of the cortisol production pathway. If these ‘unloved’ animals are treated with TSA, the first histone deacetylase inhibitor to be identified, they grow up much less stressed. They react much more like the animals who received lots of maternal care. The levels of DNA methylation at the cortisol receptor gene in the hippocampus go down, increasing expression of the receptor and improving the sensitivity of the all-important negative feedback loop. This is presumed to be because of cross-talk between the histone acetylation and DNA methylation pathways[220].

In the social defeat model in mice, the susceptible animals were treated with an SSRI anti-depressant drug. After three weeks of treatment, their behaviour was much more like that of the resilient mice. But treatment with this anti-depressant drug didn’t just result in increased levels of serotonin in the brain. The anti-depressant treatment also led to increased DNA methylation at the promoter of the corticotrophin-releasing hormone.

These studies are all very consistent with a model where there is cross-talk between the immediate signals from the neurotransmitters, and the longer-term effects on cell function mediated by epigenetic enzymes. When depressed patients are treated with SSRI drugs, the serotonin levels in the brain begin to rise, and signal more strongly to the neurons. The animal work described in the last paragraph suggests that it takes a few weeks for these signals to trigger all the pathways that ultimately result in the altered pattern of epigenetic modifications in the cells. This stage is essential for restoring normal brain function.

Epigenetics is also a reasonable hypothesis to explain another interesting but distressing feature of severe depression. If you have suffered from depression once, you are at a significantly higher risk than the general population of suffering from it again at some time in the future. It’s likely that some epigenetic modifications are exceptionally difficult to reverse, and leave the neurons primed to be more vulnerable to another bout.

The jury’s out

So far, so good. Everything looks very consistent with our theory about life experiences having sustained and long-lasting effects on behaviour, through epigenetics. And yet, here’s the thing: this whole area, sometimes called neuro-epigenetics, is probably the most scientifically contentious field in the whole of epigenetic research.

To get a sense of just how controversial, consider this. We’ve met Professor Adrian Bird in this book before. He is acknowledged as the father of the DNA methylation field. Another scientist with a very strong reputation in the science behind DNA methylation is Professor Tim Bestor from Columbia University Medical Center in New York. Adrian and Tim are about the same age, of similar physical type, and both are thoughtful and low key in conversation. And they seem to disagree on almost every issue in DNA methylation. Go to any conference where they are both scheduled in the same session and you are guaranteed to witness inspiring and impassioned debate between the two men. Yet the one thing they both seem to agree on publicly is their scepticism about some of the reports in the neuro-epigenetics field[221].

There are three reasons why they, and many of their colleagues, are so sceptical. The first is that many of the epigenetic changes that have been observed are relatively small. The sceptics are unconvinced that such small molecular changes could lead to such pronounced phenotypes. They argue that just because the changes are present, it doesn’t mean they’re necessarily having a functional effect. They worry that the alterations in epigenetic modifications are simply correlative, not causative.