Finding the Brain Cells That Make Popular Antidepressants Work

(Originally published by Columbia University)

October 5, 2015

Drugs like Prozac (collectively known as SSRIs, or selective serotonin reuptake inhibitors) are known to relieve depression by increasing the amount of serotonin in the brain.

But beyond that, the details of how the SSRIs work are fuzzy. Serotonin activates 14 different types of receptors in the brain that are spread throughout hundreds of different types of cells. Which of these cells and receptors are responsible for triggering the relief of symptoms?

A new study in mice by René Hen, PhD, professor of psychiatry, neuroscience, and pharmacology at Columbia University and a member of the Kavli Institute for Brain Science, now shows that fluoxetine (Prozac’s generic name) must act on cells in the brain’s dentate gyrus (a part of the hippocampus) in order to work.

The dentate gyrus (DG) is an extraordinary part of the brain, one of only two locations in the mammalian brain where new neurons are created after birth. About 10 years ago, Dr. Hen discovered that those new adult-born neurons were responsible for alleviating some symptoms of depression in mice, but not others. (In mice, scientists measure depression by observing different behaviors, like willingness to explore new environments, loss of appetite, or resilience when faced with a seemingly impossible task).

The new research shows that the DG’s mature cells (those created before birth or at least eight weeks old) enable all of fluoxetine’s antidepressant effects in mice, via the cells’ 1A serotonin receptors. When the researchers created a strain of mice with mature DG cells lacking 1A serotonin receptors, fluoxetine had no effect on the animals’ depression-like behaviors.

The mature cells are also responsible for boosting the birth rate of new DG neurons. “We need both the young and the mature cells for a complete response,” Dr. Hen says.

The findings should help researchers discover new ways to treat depression, especially in people who do not respond to fluoxetine and other SSRIs.

“About 50 percent of people with depression do not respond to SSRIs and, for some, the reason may stem from variations in the serotonin system. They may have slightly different receptors, or those receptors may be distributed differently. If we directly target these mature cells in the dentate gyrus, we may bypass these problems.”

The findings were published online Sept. 21 in Nature Neuroscience.

René Hen, PhD, is professor of psychiatry, neuroscience, and pharmacology; director of the Division of Integrative Neuroscience at New York State Psychiatric Institute; and a member of the Kavli Institute for Brain Science. He receives compensation as a consultant for Lundbeck and Roche.

This work was supported by the National Institute of Mental Health (grants R37MH068542, R01MH083862, K01MH098188, T32MH015144, and R01MH091844); Hope for Depression Research Foundation (grant MPPN8883), New York State Stem Cell Science (NYSTEM grant C029157), Brain and Behavior Research Foundation (NARSAD Young Investigator 19658), a Charles H. Revson fellowship, a German Research Foundation (DFG) postdoctoral fellowship, the European Molecular Biology Laboratory, and an European Commission Marie Curie Fellowship.