Нейральные стволовые клетки и действие антидепрессантов
Grigori Enikolopov, Cold Spring Harbor Laboratory, Cold Spring Harbor , New York
Neural stem cells and effects of antidepressants
A major unresolved issue in the neurogenic action of antidepressant therapies is identifying the cellular targets of their action, i.e., the steps within the neuronal differentiation cascade targeted by antidepressant drugs or treatments. Such information is crucial, since particular targets (e.g., stem cells vs. early progenitors vs. advanced neuroblasts) may imply different molecular mechanisms for controlling cell division and survival, different circuits affected by the therapies, and different insights on the behavioral action of these therapies.
We have developed a novel approach to identify and quantify the cellular targets of any neurogenic agent and we have used it to determine the cell population targeted by fluoxetine in the adult and juvenile brain. We generated several reporter mouse lines which allow us to quantitatively assess changes in stem and progenitor cells of the adult or developing brain. We then used these reporter lines to define discrete steps in the neuronal differentiation cascade (leading from stem cells to differentiated granule neurons), based on the morphology of the cells, the marker proteins that they express, and their mitotic activity, thus generating the most complete current scheme of the differentiation cascade in the adult hippocampus. We next used this line and the elucidated scheme of the differentiation cascade to determine the target of action of fluoxetine in the adult and juvenile hippocampus. We found that fluoxetine does not affect division of stem-like cells in the dentate gyrus, but increases symmetric divisions of an early progenitor cell class. We further demonstrated that this is the sole class of neuronal progenitors targeted by fluoxetine in the adult brain, and that the fluoxetine-induced increase in new neurons arises as a result of the expansion of this cell class.
Thus, these results identify a specific functional target of fluoxetine, link an early progenitor cell class to the action of SSRI antidepressants and, importantly, suggest a general strategy to explore the changes induced by other antidepressant treatments. We are currently using this approach to determine the targets of action of the main families of antidepressant drugs, electroconvulsive shock, and deep brain stimulation in the developing, juvenile, adult, and aging brain, with the goal of identifying common mechanisms of action of different antidepressant therapies and obtaining insights on the possible role of neurogenesis in anxiety and depression.
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* Encinas JM, Vaahtokari A, Enikolopov G. - Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8233-8