Encinas JM, Vaahtokari A, Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc Nat Acad Sci USA 103: 8233-8238

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2006; 103(21):8233-8. DOI: 10.1073/pnas.0601992103
Source: PubMed


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.

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    • "Neural stem cells change fate and undergo asymmetric regenerative divisions to generate both neural stem cells and neurons, which then organize into nascent circuits. Further cell fate changes occur when neural stem cells become quiescent or exit the cell cycle and differentiate into either neurons or astrocytes (Encinas et al., 2006). These cell fate decisions are essential events that control the patterning of the developing brain and ultimately affect brain function (Geschwind and Rakic, 2013; Kriegstein et al., 2006). "
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    ABSTRACT: Neurogenesis in the brain of Xenopus laevis continues throughout larval stages of development. We developed a 2-tier screen to identify candidate genes controlling neurogenesis in Xenopus optic tectum in vivo. First, microarray and NanoString analyses were used to identify candidate genes that were differentially expressed in Sox2-expressing neural progenitor cells or their neuronal progeny. Then an in vivo, time-lapse imaging-based screen was used to test whether morpholinos against 34 candidate genes altered neural progenitor cell proliferation or neuronal differentiation over 3 days in the optic tectum of intact Xenopus tadpoles. We co-electroporated antisense morpholino oligonucleotides against each of the candidate genes with a plasmid that drives GFP expression in Sox2-expressing neural progenitor cells and quantified the effects of morpholinos on neurogenesis. Of the 34 morpholinos tested, 24 altered neural progenitor cell proliferation or neuronal differentiation. The candidates which were tagged as differentially expressed and validated by the in vivo imaging screen include actn1, arl9, eif3a, elk4, ephb1, fmr1-a, fxr1-1, fbxw7, fgf2, gstp1, hat1, hspa5, lsm6, mecp2, mmp9, and prkaca. Several of these candidates, including fgf2 and elk4, have known or proposed neurogenic functions, thereby validating our strategy to identify candidates. Several candidates that we tested in the morpholino screen had no previously demonstrated neurogenic functions, including gstp1, hspa5, and lsm6, suggesting that our screen effectively identified unknown neurogenic candidates. Several of the candidate neurogenic genes have been previously implicated as human disease genes, such as mecp2 and fmr1-a, or in pathways related to disease genes, providing the groundwork to use Xenopus as an experimental system to probe conserved disease mechanisms.Together the data identify candidate neurogenic regulatory genes and demonstrate that Xenopus is an effective experimental animal to identify and characterize genes that regulate neural progenitor cell proliferation and differentiation in vivo. Copyright © 2015. Published by Elsevier Inc.
    Developmental Biology 03/2015; 4. DOI:10.1016/j.ydbio.2015.03.010 · 3.55 Impact Factor
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    • "By 1 month after birth, new neurons cease expressing young-neuron-related proteins such as DCX and PSA-NCAM, whereas the proportion of cells expressing calbindin and the neuronal nuclear antigen NeuN increases ( von Bohlen and Halbach, 2007 , 2011 ; Jagasia et al., 2009 ; Snyder et al., 2009 ). Thus, the process of transforming a neural stem cell into a mature neuron, at least in terms of its histochemical profile, takes 25 – 30 days ( Encinas et al., 2006 ). In combination with electrophysiological and morphological studies, it has been shown that at this time point, newly born neurons are at a functional state that resembles that of preexisting mature granule neurons (see below). "
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    ABSTRACT: Hippocampal neurogenesis occurs in the adult brain in various species, including humans. A compelling question that arose when neurogenesis was accepted to occur in the adult dentate gyrus (DG) is whether new neurons become functionally relevant over time, which is key for interpreting their potential contributions to synaptic circuitry. The functional state of adult-born neurons has been evaluated using various methodological approaches, which have, in turn, yielded seemingly conflicting results regarding the timing of maturation and functional integration. Here, we review the contributions of different methodological approaches to addressing the maturation process of adult-born neurons and their functional state, discussing the contributions and limitations of each method. We aim to provide a framework for interpreting results based on the approaches currently used in neuroscience for evaluating functional integration. As shown by the experimental evidence, adult-born neurons are prone to respond from early stages, even when they are not yet fully integrated into circuits. The ongoing integration process for the newborn neurons is characterised by different features. However, they may contribute differently to the network depending on their maturation stage. When combined, the strategies used to date convey a comprehensive view of the functional development of newly born neurons while providing a framework for approaching the critical time at which new neurons become functionally integrated and influence brain function.
    Reviews in the neurosciences 03/2015; DOI:10.1515/revneuro-2014-0071 · 3.33 Impact Factor
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    • "Increased survival or newly generated neurons at baseline [45] Tph2 −/− mouse Normal baseline proliferation in serotonin deficient mice [75] Tph2KI mouse Increased survival or newly generated neurons at baseline with increased numbers of DCX-positive cells Antidepressant action and neurogenesis [57] Flx First shown increase in neurogenesis after prolonged treatment with Flx [14] cAMP cAMP signal transduction cascade contributes to increased neurogenesis as antidepressant response [16] Tianeptine Treatment reduces proliferation of precursor cells in the DG [79] 5-HT1A KO Flx 5-HT1A receptors are required for Flx-induced hippocampal neurogenesis [25] Flx Flx acts solely on type-2a progenitors by increasing the rate of symmetric cell divisions [88] Flx Chronic treatment accelerates maturation and synaptogenesis of immature granule cells [6] SSRI Acute BDNF injection into the hippocampus increases SERT function [83] 5-HT2C Increases proliferation and mediates the antidepressant effect of agomelatine [44] 5-HT1A, 5-HT2C Latency of Flx action due to additive effects of 5HT1A, 2C receptors [47] 5-HT4 KO Flx Flx treatment reverses neuronal maturation (Calbindin expression) with up-regulated 5-HT4 signaling [20] 5-HT2B Pharmacological receptor stimulation mimics SSRI-like response [11] SSRI, TCA Stimulation of angiogenesis and neurogenesis [27] RNAi – SERT Acute SERT silencing increases 5-HT release and neurogenesis and decreases latency in antidepressant action [85] BDNF Decreased BDNF mRNA levels in the DG after 5-HT2A and 2C chronic agonist treatment [18] BDNF BDNF potentiates the effect of SSRI treatment (in vivo intracerebral microdialysis) [71] BDNF SSRI treatment increases BDNF levels released from astrocytes that promote neurogenesis Functional role of serotonin in adult neurogenesis [74] SSRI, BDNF, exercise Exercise-plus-antidepressant challenge lead to increased BDNF levels in the hippocampus [45] Tph2 −/− mouse No running-induced effect on proliferation when serotonin is absent serotonin deficiency has no effect on baseline neurogenesis that may be compensated by altered neurotrophic/BDNF signaling. We have proposed BDNF as candidate for permanent compensation in serotonin deficient mice and recent data already reveal enhanced BDNF mRNA levels in Tph2 −/− and Tph2KI mice [61] [75], although accompanied by increased serotonin fiber density in the hilus. "
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    ABSTRACT: Serotonin is probably best known for its role in conveying a sense of contentedness and happiness. It is one of the most unique and pharmacologically complex monoamines in both the peripheral and central nervous system (CNS). Serotonin has become in focus of interest for the treatment of depression with multiple serotonin-mimetic and modulators of adult neurogenesis used clinically. Here we will take a broad view of serotonin from development to its physiological role as a neurotransmitter and its contribution to homeostasis of the adult rodent hippocampus. This chapter reflects the most significant findings on cellular and molecular mechanisms from neuroscientists in the field over the last two decades. We illustrate the action of serotonin by highlighting basic receptor targeting studies, and how receptors impact brain function. We give an overview of recent genetically modified mouse models that differ in serotonin availability and focus on the role of the monoamine in antidepressant response. We conclude with a synthesis of the most recent data surrounding the role of serotonin in activity and hippocampal neurogenesis. This synopsis sheds light on the mechanisms and potential therapeutic model by which serotonin plays a critical role in the maintenance of mood.
    Behavioural Brain Research 08/2014; DOI:10.1016/j.bbr.2014.07.038 · 3.03 Impact Factor
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