Epigenetics May Be Reason For Ineffective Depression Treatment

According to the World Health Organization (WHO), over 264 million people worldwide are affected by depression at any point in time. Each year, about 800,000 people die by suicide, which is also the second leading cause of death in people between the ages of 15 and 29 years old.

 Depression is a crippling illness that can affect anybody at any time. Understanding the molecular and genetic factors at play in depression is critical to developing effective treatment methods to address it and help bring these numbers of incidence and mortality down, while also recognizing that there are various contributing factors to the disease—not just one single cause or trigger.

One key factor already identified is ongoing inflammation, particularly within the blood-brain barrier (BBB). Through complex vasculature combined with its physical placement within the brain, the BBB controls the flow of materials into and out of the brain, providing not only nutrition and waste collection functions but also protecting the brain from foreign pathogens.

Scientists from the Cervo Brain Research Centre in Quebec City wanted to determine the underlying mechanisms involved in controlling the efficiency of the BBB. They found that epigenetics may play a large role in helping to restore it’s correct function.

The immune system also plays a role here, close and ready to protect the brain from infection and illness; for example, it can trigger local inflammatory responses if it suspects a potential pathogen is trying to enter to access the brain.

But clinical studies have shown that it’s not just a physical pathogen that can have this effect. Chronic stress can cause ongoing inflammation that, over time, erodes the BBB by triggering the loss of junction proteins such as claudin-5 (cldn5). Without junction proteins effectively regulating access, inflammatory cytokines (among other things) can circulate relatively uncontrolled. This can contribute to the depressive symptoms seen in illnesses such as Major Depressive Disorder (MDD).

Where else do we think about chemical access across various barriers in the body? Medicine—as in pharmaceuticals and pharmacology—tackles this problem constantly, and the question of how to control substance access across various membranes; testing doses, for example, can tell a lot about how well a drug is being absorbed and how effective it is. 

“Between 30% and 50% of those suffering from depression respond either poorly or not at all to antidepressants,” claims Caroline Ménard, lead author of the study. a professor at Université Laval’s Faculty of Medicine as well as a researcher at the.

From this statistic, Ménard and her team knew that antidepressants needed to be optimized further in order to be more effective, but more significantly they realized that there must be some other factors contributing to the obstruction of depressants—and the persistence of depression. “This suggests that biological mechanisms other than those directly affecting neurons are at play.”

Having previously shown that BBB permeability was positively correlated to the emergence of depressive symptoms, which was associated with an increase in claudin-5, Ménard and her team took a fresh look at three groups of mice: normal control mice, depressed stressed mice, and resilient stressed mice.

These groups could shed light not only on what contributes to depression, but also how it can be avoided. Using molecular biology methods, they analyzed brain tissue samples from the mice in each of these three groups to dig deeper into claudin-5 expression as well as proteins adjacent to it.

Depressed mice showed increased expression of HDAC1, an enzyme that regulates histone acetylation, which reduced claudin-5 levels, resulting in an increase to BBB permeability. 

The team found that the resilient mice demonstrated lower amounts of FOXO1, a transcription factor known to repress cldn5. This resulted in a higher concentration of cldn5, and less BBB permeability.  

Using tissue samples from the Douglas Bell Canada Brain Bank, Ménard and her research team were able to confirm these results applied to humans as well; so what’s next? While existing antidepressants focus heavily on directly targeting neurons, the neurons’ environment—as controlled by the BBB—needs to be considered as well. Reducing the permeability of the blood-brain barrier in depressed patients, either through pharmaceutical intervention or maybe even lifestyle changes, could help treat depression.

If you or a loved one is struggling with depression, please visit This Way Up for help.

Source:  Menard C. et al. (2019). Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression.  PNAS 117 (6) 3326-3336

Reference: Jean-François Huppé “Treatment for depression must also restore proper functioning of the blood–brain barrier” Université Laval. 20 Jan. 2020. Web.

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About Andrea P 30 Articles
Andrea received her B.S. in Biology with minors in Chemistry and Neuroscience from Duke University. She first fell in love with biology when she learned about the magnificent powers of protein folding, and then naturally wanted to know who was in charge. She’s fascinated by the finer controls of epigenetic modifications. In her downtime, she enjoys hiking with her dog and going for long drives to explore new places.


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