The serotonin transporter (SERT) is a molecule that regulates concentrations of the neurotransmitter serotonin. Certain genes control how SERT is expressed, and any disruption in the expression of these genes can lead to disorders like autism, ADHD, bipolar disorder, and depression. Now, a new study by Duke University researchers has found that the presence of a chemical mark atop the SERT’s DNA can affect the way a person's brain responds to threats.

The study appears in the online edition of Nature Neuroscience. It highlights that stress and stress-related psychiatric disorders can be caused by not only genetics but chemical imbalances too. Serotonin is a monoamine neurotransmitter that is synthesized by the serotonergic neurons in the central nervous system. Its various functions include regulation of mood, appetite, and sleep. Decreased levels of serotonin are thought to cause mild to severe depression.

The SERT is a monoamine transporter protein that transports serotonin between neurons in the brain. In the 1990s, scientists discovered that a degenerate polymorphism that occurs in the gene responsible for coding the serotonin transporter gives some individuals exaggerated responses to stress, including the development of depression. Since then, it has become a primary target for drugs that treat psychiatric disorders.

Sitting on top of the SERT's DNA (and studding the entire genome), are chemical marks called methyl groups that help regulate where and when a gene is active, or expressed. DNA methylation or the addition of methyl groups to the DNA is one form of epigenetic modification scientists are studying in order to understand how the same genetic code can produce so many different cells and tissues, as well as differences between individuals as closely related as twins.

In looking for methylation differences, "we decided to start with the serotonin transporter because we know a lot about it biologically, pharmacologically, behaviorally, and it's one of the best characterized genes in neuroscience," said senior author Ahmad Hariri, from the Duke Institute for Brain Sciences, in a statement. "If we're going to make claims about the importance of epigenetics in the human brain, we wanted to start with a gene that we have a fairly good understanding of." 

Eighty college-aged participants of the Duke Neurogenetics Study (DNS) underwent non-invasive brain imaging procedures. They were showed pictures of angry or fearful faces, and researchers watched for responses in a region of the brain called the amygdala, which helps shape our behavioral and biological responses to threat and stress. The amount of methylation on the SERT DNA was then measured from their saliva samples.

The team found a direct correlation between the amount of methylation and activity in the amygdala. Increased activity in this brain region contributed to an exaggerated stress response and vulnerability to stress-related disorders, the study found. Even small variations in methylation between individuals was enough to create differences between their respective amygdala activity. The amount of methylation was a better predictor of amygdala activity than DNA sequence variation, which had previously been associated with risk for depression and anxiety.

To further corroborate their findings, the team again measured amygdala activity when shown angry and fearful faces, as well as methylation of the SERT gene isolated from blood in 96 adolescents aged 11 and 15. The analyses revealed an even stronger link between methylation and amygdala activity. "Now, over 10 percent of the differences in amygdala function mapped onto these small differences in methylation," Hariri said. The DNS study had found just under seven percent. 

Furthermore, when they analyzed patterns of methylation in the brains of dead people, they found that methylation of a single spot in the SERT gene was associated with lower levels of SERT expression in the amygdala. The team concluded that higher methylation may result in a lower ability to read the gene, as it dampens gene expression, which in turn alters serotonin signaling and affects amygdala activity.  

Since the methylation patterns isolated from saliva, blood, and the brain were the same, the study suggests a hereditary link in which the patterns are passed on. The team hopes that DNA methylation will now be the focus of targeted therapeutic research.

Source: Hariri A, Nikolova Y, Koenen K, et.al. Beyond genotype: serotonin transporter epigenetic modification predicts human brain function. Nature Neuroscience. 2014.