Study uncovers key to antidepressant response

February 7, 2013, Johns Hopkins University School of Medicine
sFRP3 acts as a gatekeeper that links brain activity to new neuron growth. Proliferating progenitor neurons are shown in blue, immature neurons in green, and mature neurons in red. Credit: Max Song and Maggie Song

Through a series of investigations in mice and humans, Johns Hopkins researchers have identified a protein that appears to be the target of both antidepressant drugs and electroconvulsive therapy. Results of their experiments explain how these therapies likely work to relieve depression by stimulating stem cells in the brain to grow and mature. In addition, the researchers say, these experiments raise the possibility of predicting individual people's response to depression therapy, and fine-tuning treatment accordingly. Reports on separate aspects of the research were published in December on the Molecular Psychiatry website, and will also appear in the Feb. 7 issue of Cell Stem Cell.

"Previous studies have shown that antidepressants and both activate neural stem cells in the to divide and form new neurons," says Hongjun Song, Ph.D., a professor of neurology and director of the Stem Cell Program at the Johns Hopkins University School of Medicine's Institute for . "What were missing were the specific molecules linking antidepressant treatment and stem cell activation."

To make that link, Song's team and its collaborators assembled a body of evidence from different types of experiments. In one, they compared gene activity in the brains of mice that had and had not been treated with electroconvulsive therapy, looking specifically at genes with protein products that are known to regulate neural stem cells. The comparison turned up differences in the activity of one inhibitor gene for a chemical chain reaction that had been previously implicated in stimulating . Specifically, the therapy reduced the amount of protein the inhibitor gene, sFRP3, produced, which would in turn have given the growth-stimulating chain reaction freer rein.

To learn more about sFRP3's effects, the team next compared normal mice with mice that had been engineered to lack the sFRP3 protein. They found that the modified mice behaved like normal mice on antidepressants; moreover, giving antidepressants to the modified mice did not further change their behavior. This strongly suggested that antidepressants work by blocking sFRP3; without sFRP3, the modified mice had nothing to block.

In order to tie their mouse work to what happens in the human brain, the researchers next analyzed genetic information from 541 depression patients and tracked their response to a course of . The team found three common variations in the human version of sFRP3 that were linked to a better response to therapy. Wondering what these variations actually did, the researchers searched a database that correlates gene sequences to gene activity in the human brain. All three variations caused less gene activity, they found, meaning that there likely would have been less inhibitor.

Song notes that sFRP3 is also regulated by other conditions, including exercise. "This gene's activity is very sensitive to the amount of activity in the brain, so sFRP3 seems to be a gatekeeper that links activity to new neuron growth," he says. The finding has two major near-term implications, he says: It could lead to genetic tests that enable doctors to predict a patient's response to antidepressants, and it provides a target for potential new therapies for the disease.

Explore further: Brain's stem cells 'eavesdrop' to find out when to act

More information: www.nature.com/mp/journal/vaop … full/mp2012158a.html

Related Stories

Brain's stem cells 'eavesdrop' to find out when to act

August 6, 2012
Working with mice, Johns Hopkins researchers say they have figured out how stem cells found in a part of the brain responsible for learning, memory and mood regulation decide to remain dormant or create new brain cells. Apparently, ...

Scientists discover 'fickle' DNA changes in brain

September 30, 2011
Johns Hopkins scientists investigating chemical modifications across the genomes of adult mice have discovered that DNA modifications in non-dividing brain cells, thought to be inherently stable, instead underwent large-scale ...

Nervous system stem cells can replace themselves, give rise to variety of cell types, even amplify

June 30, 2011
(Medical Xpress) -- A Johns Hopkins team has discovered in young adult mice that a lone brain stem cell is capable not only of replacing itself and giving rise to specialized neurons and glia – important types of brain ...

Recommended for you

Intensive behavior therapy no better than conventional support in treating teenagers with antisocial behavior

January 19, 2018
Research led by UCL has found that intensive and costly multisystemic therapy is no better than conventional therapy in treating teenagers with moderate to severe antisocial behaviour.

Babies' babbling betters brains, language

January 18, 2018
Babies are adept at getting what they need - including an education. New research shows that babies organize mothers' verbal responses, which promotes more effective language instruction, and infant babbling is the key.

College branding makes beer more salient to underage students

January 18, 2018
In recent years, major beer companies have tried to capitalize on the salience of students' university affiliations, unveiling marketing campaigns and products—such as "fan cans," store displays, and billboard ads—that ...

Inherited IQ can increase in early childhood

January 18, 2018
When it comes to intelligence, environment and education matter – more than we think.

Modulating molecules: Study shows oxytocin helps the brain to modulate social signals

January 17, 2018
Between sights, sounds, smells and other senses, the brain is flooded with stimuli on a moment-to-moment basis. How can it sort through the flood of information to decide what is important and what can be relegated to the ...

Baby brains help infants figure it out before they try it out

January 17, 2018
Babies often amaze their parents when they seemingly learn new skills overnight—how to walk, for example. But their brains were probably prepping for those tasks long before their first steps occurred, according to researchers.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.