Beyond an Individual Burden: Epigenetics, Heritability,and Depression

By Neha Patel

Earlier this month, my friend Kristin wrote a great blog about epigenetic changes that occur during stressful times in childhood and adolescence, and how they contribute to adult-onset psychiatric disorders. In this blog, I’m going to focus on the fact that these epigenetic modifications are heritable, and may have larger implications for communities and their future generations.

Forced swim test (Source)

In a paper published in 2010 by Franklin et al., during postnatal days 1-14, one group of mice were exposed to unpredictable maternal separation and unpredictable maternal stress (MSUS). The other group was the control, with their mother present and an unstressed environment. This F1 generation was later put through behavioral testing as adults. The F1 adults that were exposed to MSUS showed signs of depression, indicated by more time spent floating during a forced swim test, and also a lack of behavioral control, which was shown by a shorter latency to enter the center of an open field.

However, none of this is new to us. Of course a mouse that experienced early stress would most likely be depressed and have abnormal behavior in adulthood! The troubling part is the next step in the authors’ experiment, when they mated both F1 males (the MSUS and control) to unstressed females. The pups of the F2 generation were all reared like the F1 control, with no early stress, and once again behaviorally tested as adults. The results determined that some of them had signs of depressive behavior, particularly the females, despite being raised with love. The authors suggest that this is in line with the complicated sex-dependent mechanism seen in humans.  Luckily, treatment with an antidepressant was able to reverse these behaviors in mice.

Fig. 1A in Franklin et al. paper. This shows the experimental design for the breeding of mice. Blue mice are control, and orange are MSUS. Black mice are the unstressed females subsequent generations are mated with.

To produce a subsequent generation of offspring (F3), the authors’ mated control and MSUS F2 males and unstressed females, and found that the females were still displaying depressive behavior. The lab turned to molecular techniques to determine whether there were epigenetic changes that may have persisted through the male germline cells all the way from the F1 generation. The candidate genes that were chosen are involved in epigenetic changes in gene expression, and linked with depression. Methyl CpG-binding protein 2 (MeCP2), a gene which is associated with an increased stress response when its’ expression is deficient, was analyzed by bisulfite pyrosequencing to be hypermethylated in both the F1 MSUS sperm, and the F2 female brains. The hypermethylation is indicative of downregulation of expression, which was confirmed with quantitative RT-PCR, a technique which can quantify levels of mRNA. Other candidates, such as the cannabinoid receptor-1 (CB1), and corticotrophin-releasing factor receptor 2 (CRFR2), were also shown to be differentially methylated and downregulated in gene expression in F1 MSUS sperm and F2 progeny female brains. The downregulation of all these genes can contribute to the depressive-like behavior in mice.

In conclusion, this paper shows that early postnatal stress can alter methylation patterns in key behavioral genes in the germline of males. Since these changes are in the germline, these patterns can persist through generations and impact the behavior of offspring.  This study was done in mice, but what would the impact be for humans if the same mechanism was conserved?

Children at the Internment Camp Minidoka in Idaho. (Source)

Many communities have been impacted throughout history by stress and separation. To name a few examples, the Holocaust, Japanese Internment, and the refugee experiences of Vietnamese people all were stressful events for these respective communities, and often resulted in separation of family. Also, children who grow up in poverty experience more stress, and are likely separated from their caretakers more often if these caretakers are taking on multiple jobs to make ends meet. Foster children are another population that are of concern when we are talking about a possible impact of this research—the instability they experience from an early age can upset their lives. This research also suggests that even if stability is reached later in life, the epigenetic modifications can still remain and effect future generations.

So what can we do as a society to help alleviate these negative consequences in certain communities? For one, we have to be as supportive and nonjudgmental of others as we can. We don’t know their life history or even their family’s life circumstances before we come into contact with them. As Heather suggested in her insightful blog post, we should try and err on the side of compassion. Also, we should speak up if we see an injustice against a community because turning a blind eye may very well result in future harm for many generations to come.

References:

Franklin, T.B., H. Russig, I.C. Weiss, J. Gräff, N. Linder, A. Michalon, S. Vizi, and I.M. Mansuy. 2010. Epigenetic transmission of the impact of early stress across generations. Biological Psychiatry 68:408-415.

Thayer, Z.M., and C.W. Kuzawa. 2011. Biological memories of past environments; epigenetic pathways to health disparities. Epigenetics 6:798-803.

Trasler, J.M. 2009. Epigenetics in Spermatogenesis. Molecular and Cellular Endocrinology 306: 33-36.