It has been well known for many years that chronic treatment with selective serotonin reuptake inhibitors (SSRIs) increases neurogenesis in the adult hippocampus. This increase in the production of new neurons is likely to relieve the symptoms of depression by somehow causing more neurons to be present in the dentate gyrus. But the cellular basis for the action of SSRIs, as well as which class of cells within the neuronal differentiation cascade is targeted by antidepressant drugs, has not been fully understood. Reporting in the May 23 Proceedings of the National Academy of Sciences, researchers have demonstrated that the SSRI antidepressant fluoxetine "does not affect division of stem-like cells in the adult dentate gyrus but increases symmetric divisions of an early progenitor cell class."

Grigori Enikolopov, PhD, an Associate Professor at Cold Spring Harbor Laboratory in New York, and colleagues created a transgenic mouse line that allowed the identification, classification, and easy quantification of "distinct classes of cells that comprise discrete steps in the differentiation cascade between neuronal stem cells and fully differentiated granule neurons [in the adult brain]." Fluoxetine-induced changes were examined in each of these classes of cells by treating mice with either distilled water or fluoxetine (10 mg/kg/day) for 15 days and monitoring select cell populations either 24 hours or 30 days later. Dividing cells were labeled with 5-bromo-2’-deoxyuridine (BrdU), which was injected into the animals on the last day of treatment. This approach allowed the investigators to show that "fluoxetine affects a specific step of [the neuronal differentiation cascade] in the adult brain, increasing symmetric divisions of a particular early neural progenitor class in the dentate gyrus."

A DEFINED TARGET

Dr. Enikolopov and his colleagues reported that "the number of BrdU-labeled cells in the dentate gyrus was increased by 40.9% after fluoxetine administration, in line with previous reports on the effects of chronic treatment with the drug." Labeling with cyan fluorescent protein and glial fibrillary acidic protein, in addition to BrdU, indicated that the number of BrdU-labeled quiescent neural progenitor (QNP) cells was not affected by fluoxetine treatment, whereas the number of BrdU-labeled amplifying neural progenitor (ANP) cells increased by 46.4%.

"These results indicate that the rate of QNP cell division is unchanged and that fluoxetine increases symmetric divisions of ANP cells. When considered together with the data on other cell classes, these results suggest that ANPs are the only class of precursor cells in the dentate gyrus that directly respond to fluoxetine," the researchers stated. In addition, analyses of changes in the subventricular zone showed that "the fluoxetine-induced increase in the number of early progenitor cells is specific for the dentate gyrus and does not affect the subventricular zone."

Dr. Enikolopov commented, "We believe that by identifying the target of a prototype antidepressant, these results will help [investigators] design new antidepressant drugs and therapies with higher precision, fewer side effects, or greater potency. They may also help to design faster procedures to screen for drugs with a potential antidepressant effect."

ADDITIONAL RESEARCH

According to Dr. Enikolopov, further research is needed to improve classification of subclasses of precursor cells in the dentate gyrus. He and his colleagues noted that findings from transcriptional profiling studies "suggest that ANPs can be further subdivided into smaller subpopulations, perhaps reflecting progressive division cycles."

Dr. Enikolopov’s group is currently assessing fluoxetine’s effects on fetal and adolescent brain development, as well as whether other treatments for depression—such as non-SSRIs, electroconvulsive shock, and deep brain stimulation—target the same or different neural progenitor cell classes as fluoxetine. Dr. Enikolopov hopes that this research will help clarify whether fluoxetine acts on the same class of progenitor cells in the developing brain as in the adult brain and if completely dissimilar antidepressant treatments converge on one cell type. "This may have direct relevance for understanding the biologic basis of depression and for designing new therapies," he said.

—Karen L. Spittler

Suggested Reading
Encinas JM, Vaahtokari A, Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci U S A. 2006;103:8233-8238.

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