Boosting the activity of newly-created neurons mimicked the effect of antidepressant medication in animal models, according to a recent Northwestern Medicine study published in Nature Communications.
The discovery may point to a new understanding of how to treat depression, said John Kessler, MD, the Ken and Ruth Davee Professor of Stem Cell Biology and senior author of the study.
“To develop treatments, you have to know where the lever is before you can pull it,” said Kessler, who is also a professor of Neurology in the Division of Comprehensive Neurology and of Pharmacology. “This study gives us a whole new target.”
The effects of depression are well-documented, but its causal mechanisms are still up for debate, according to Kessler. Most scientists agree that chemical imbalances in the brain are a primary factor, but the source of those imbalances remains murky.
Some evidence implicates changes in the rate of neurogenesis, the process by which new neurons are created from specialized neural stem cells in the hippocampus, Kessler explained.
“There are quite a number of things which alter neurogenesis and alter behavior at the same time,” Kessler said. “For example, running and exercise, enriched social environments or antidepressant drugs can increase neurogenesis, and stress can decrease it.”
Neurogenesis is most active during embryonic redevelopment, but it doesn’t stop after birth, as the hippocampus continues to produce neurons throughout life, albeit at a slower rate. Changing production of new neurons could affect behavior, but this idea is still unproven, according to Kessler.
“Many people say the number of new neurons is just too small, and not wired up enough in the brain to exert all of these effects on behavior,” Kessler said.
Kessler, along with Elif Tunc-Ozcan, PhD, a postdoctoral fellow in the Kessler laboratory and lead author of the study, set out to test if neurogenesis could directly alter depression symptoms. The investigators genetically altered mice so neurons created in adulthood had a kill switch, a receptor that could be activated by a drug.
When neurogenesis was silenced, the scientists found anti-depressant drugs no longer worked, speaking to neurogenesis’ importance in modulating depression-like symptoms. Next, in a similar but opposite experiment, the investigators inserted an excitatory receptor into the newly created neurons.
When they activated this receptor, it was as if the mice were treated with Prozac, according to Tunc-Ozcan. This was surprising because they hadn’t increased neuron production, just boosted neuronal activity.
“Activating these neurons was having an antidepressant effect,” Tunc-Ozcan said. “This was completely unexpected; nobody in our field had shown this before.”
These findings dovetail with a previous Kessler laboratory study, published in Molecular Psychiatry, that found hippocampal bone morphogenetic protein (BMP), a protein involved in neurogenesis, was necessary for antidepressant drugs to work.
Many of these drugs currently prescribed to patients operate by correcting various chemical imbalances in the brain, increasing production of serotonin or dopamine, for example. However, many patients have to try several different drugs before finding one that works.
Kessler said he believes that BMP may actually be upstream of other chemicals like serotonin, and would be a much better therapeutic target — instead of playing whack-a-mole with several different neurotransmitters, BMP-targeting drugs that increase activity of new neurons may work on the whole lot.
“If that is correct, it could be a whole new theory of the etiology of depression,” Kessler said.
This work was supported by National Institutes of Health grants T32 AG020506 and R01 MH114923, and by the Davee Foundation. Kessler is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
