Fluoxetine targets early progenitor cells in the adult brain

Abstract

Chronic treatment with antidepressants increases neurogenesis in the adult hippocampus. This increase in the production of new neurons may be required for the behavioral effects of antidepressants. However, it is not known which class of cells within the neuronal differentiation cascade is targeted by the drugs. We have generated a reporter mouse line, which allows identification and classification of early neuronal progenitors. It also allows accurate quantitation of changes induced by neurogenic agents in these distinct subclasses of neuronal precursors. We use this line to demonstrate that the selective serotonin reuptake inhibitor antidepressant 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 demonstrate that these cells are the sole class of neuronal progenitors targeted by fluoxetine in the adult brain and suggest that the fluoxetine-induced increase in new neurons arises as a result of the expansion of this cell class. This finding defines a cellular target for antidepressant drug therapies.hippocampus ͉ neural stem cells ͉ neurogenesis ͉ dentate gyrus ͉ antidepressants A ntidepressant drugs of the selective serotonin reuptake inhibitor (SSRI) class (e.g., fluoxetine) are commonly used to treat a wide spectrum of mood disorders in adults (1); they also are increasingly prescribed to children and adolescents (2, 3). However, the cellular basis for the action of SSRIs is not clear. In addition to its effects on neurotransmission, SSRI fluoxetine increases generation of new neurons in the dentate gyrus (DG) of the adult brain (4-9). Importantly, recent findings suggest that this increase may be a causative factor in the behavioral effects of this class of antidepressants (7). These discoveries may provide a novel framework for understanding depression and designing new therapeutic drugs. However, the step within the neuronal differentiation cascade targeted by SSRIs remains unknown. Particular targets (e.g., stem cells vs. early progenitors vs. advanced neuroblasts) may imply different molecular mechanisms of controlling cell division and survival, different circuits affected by the drugs, and different insights on the behavioral action of the drugs.One of the problems in defining SSRI targets within the neuronal proliferation-differentiation cascade is the imprecision in quantifying the changes in each class of neural precursor cells in the brain. Accurate enumeration of changes in distinct subpopulations of neuronal precursors by immunocytochemistry is problematic: High cell density, complex cell morphology, and uncertainties in defining distinct boundaries between subclasses of cells reduces the precision of evaluating changes in particular subclasses of neuronal precursors (e.g., in contrast to BrdU or thymidine labeling of cell nuclei, where great precision can be achieved); this problem is particularly acute in the young brain, where the number of neural stem and progenitor cells is particularly ...

Genetic Regulation of Behavioral and Neuronal Responses to Fluoxetine

“…Growth factors act via MAPK signaling to induce the transcription of IEGs and transcription factors that promote the proliferation of neuronal progenitor cells and the survival and differentiation of newly born neurons. A recent study has identified a specific class of neuronal precursor cells, amplifying neural progenitors that appear to be sensitive to chronic fluoxetine treatment (Encinas et al, 2006); it is possible that the straindependent effect of fluoxetine on neurogenesis is due to genetic polymorphisms associated with this type of cell.…”

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

“…Since rolipram plays its role in neurogenesis via activation of the cAMP/CREB cascade, neurogenesis induced by PDE4B deficiency likely is also mediated by cAMP signaling. Interestingly, chronic administration of the antidepressant fluoxetine, a selective serotonin reuptake inhibitor, not only increases hippocampal neurogenesis (Encinas et al, 2006;Malberg et al, 2000), but also decreases the expression of PDE4B in the brains of mice and rats (Dlaboga et al, 2006;Miro et al, 2002). However, while these findings appear to be consistent with FST behavior and hippocampal neurogenesis observed in PDE4BÀ/À mice, further studies are needed to determine their relationship to antidepressant activity.…”

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

“…7). Previous works have demonstrated that cell cycle regulation in the adult brain is precursor-type-specific [24], thus we sought to determine whether the defect in proliferation observed in Cdk6 À/À brains was restricted to a subpopulation versus all cycling precursors. First, we used glial fibrillary acidic protein (GFAP) and the Sry-related HMG box transcription factor Sox2 to identify immature DG precursors with, respectively, radial (type 1) and nonradial (type 2a) morphology that are not yet restricted to a neuronal fate [25].…”