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Cell Cycle. Author manuscript; available in PMC Jun 1, 2010.
Published in final edited form as:
Published online Jun 17, 2008.
PMCID: PMC2879159
NIHMSID: NIHMS205020
Antidepressants and Cdk inhibitors
Releasing the brake on neurogenesis?
Vera Chesnokova1,3* and Robert N. Pechnick2,3,4
1Department of Medicine; Division of Endocrinology, Cedars-Sinai Medical Center; Los Angeles, California USA
2Department of Psychiatry and Behavioral Neurosciences; Cedars-Sinai Medical Center; Los Angeles, California USA
3David Geffen School of Medicine, University of California; Los Angeles, California USA
4Brain Research Institute; University of California; Los Angeles, California USA
*Correspondence to: Vera Chesnokova; Division of Endocrinology; Cedars-Sinai Medical Center; 8700 Beverly Blvd.; Los Angeles, California 90048 USA; Tel.: 310.423.7659; Fax: 310.423.0221, chesnokovav/at/cshs.org
It is now clear that neurogenesis occurs in the brain of adult mammals. Many studies have attempted to establish relationships among neurogenesis, depression and the mechanism of action of antidepressant drugs. Therapeutic effects of antidepressants appear to be linked to increased neurogenesis in the hippocampus. Cdk inhibitors are expressed in multiple brain regions, presumably maintaining quiescence in differentiated neurons. Recently, the abundant expression of p21Cip1 was found in neuroblasts and in newly developing neurons in the subgranular zone of the hippocampus, a region where adult neurogenesis occurs. Chronic treatment with the tricyclic antidepressant imipramine markedly decreased p21Cip1 mRNA and protein levels and stimulated neurogenesis in this region. These results suggest that p21Cip1 restrains neurogenesis in the hippocampus, and antidepressant-induced stimulation of neurogenesis might be a consequence of decreased p21Cip1 expression, with the subsequent release of neuronal progenitor cells from the blockade of proliferation. These findings suggest the potential for new therapeutic strategies for the treatment of depression that target cell cycle proteins. However, there is a possibility that long-term stimulation of neurogenesis might exhaust the proliferation potentials of neuronal progenitors.
Keywords: adult neurogenesis, cell cycle regulators, p21Cip1, depression, antidepressants, neural progenitors, neuronal proliferation
For many years the production of new neurons in the brains of mammals had been considered confined to development. This implied that any loss of neurons was irreversible and inevitable because damaged or dying neurons could not be replaced in adult brain. The non-renewability of neurons was a fundamental premise underlying the pathophysiology of some neurological and neurodegenerative disorders and the responses to brain injury. The “no new neurons in adult brain” doctrine was based upon the lack of observable mitotic divisions and the absence of neurons showing a transition from an immature to a mature state in adult brain. With the development and implementation of new methodologies, such as 3H-thymidine labeling in the1960s, the presence of neurogenesis was first observed in adult mammals.1 Later, using bromodeoxyuridine (BrdU) labeling, several thousand dividing cells could be detected in the hippocampus of young adult mice.2 Of these cells, half express neuron-specific markers. The rate of generation of new neuron in young adult mice and rats has been estimated to be from 1.5% to 6% of the total hippocampal granule cell population per month. Although differences have been found between and among species, adult neurogenesis has been found in all mammals studied, including various species of rodents, nonhuman primates and humans (reviewed in refs. 36). Adult neurogenesis has decreased over evolution. Compared to nonmamalian vertebrates such as birds and reptiles, the rate and extent of neurogenesis are much lower in mammals.7 Furthermore, the rate of neurogenesis is age-dependent; it decreases from adolescence to adulthood, and is even lower in aged animals.710
Neurons are involved in information processing, whereas glia (astrocytes and oligodendrocytes) provide an essential supportive role for the neurons. Adult neural stem cells (NSC) are cells that can self-renew and differentiate into all types of neural cells, including neurons, astrocytes and oligodendrocytes.11 These properties of adult NSC have been shown in vitro, but have not been convincingly demonstrated in vivo. Therefore, these dividing cells are frequently referred to as “neural progenitors”.4 Neuronal progenitors can be isolated from many areas of the adult nervous system, but adult neurogenesis is not a global phenomenon throughout the brain, but is restricted to specific regions. Neurogenesis has been most clearly demonstrated in two brain locations: the subventricular zone (SVZ), located next to the ependyma, a thin cell layer that lines the lateral ventricles; and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. Neurons born in the adult SVZ migrate over a great distance through the rostral migratory system, eventually turning towards the granule and periglomerular cell layers in the olfactory bulb (OB). Neurons born in the adult SGZ migrate into the granular cell layer of the dentate gyrus and become granule cells.35 While neurogenesis can be stimulated in other brain regions by various conditions and insults such as injury, it remains unclear how much neurogenesis takes place in brain areas other then the SGZ and SVZ under normal conditions.4,6,12 In some species adult neurogenesis has been reported to occur in the neocortex, hypothalamus, striatum, amygdala, substantia nigra and brainstem, however, some of these findings have been disputed.6 In humans, it is generally accepted that neurogenesis occurs in the hippocampus,13 and recent evidence suggests that it also takes place in the olfactory bulb.14 The greatest controversy is whether neurogenesis occurs in nonhuman primate and human neocortex.6,1517
NSC and progenitor cells within the SGZ represent a spectrum of several distinct progenitors cell types. Using a neural progenitorspecific, nestin-GFP-expressing transgenic mouse, these cells have been defined as types 1, 2a, 2b and 3b.3,4,1821 The early neural progenitors, type 1 and 2a cells, lack committed neuronal markers and express nestin, a primitive neuroepithelial marker. In contrast, nestin expression is downregulated in late, committed neuronal progenitors or type 2b and type 3b cells; they begin to express markers of developing young neurons such as microtubule protein doublecortin (DCX) and polysialyted neural cell adhesion molecule (PS-NCAM).2022 Normally quiescent astrocyte-like type 1 cells express nestin and contain a radial glial fibrillary acidic protein (GFAP)-expressing process and are believed to represent self-renewing stem-like cells.23 Type 2 cells, which arise from asymmetric division of type 1 cells, represent fully committed neuroblasts. They express nestin but lack GFAP, and are distinguished by the absence (type 2a) or presence (type 2b) of DCX.23,24
The survival and the integration of newborn neurons in the SGZ are largely determined during a critical time window (1–3 weeks) when these neurons are immature and display unique physiological properties. Approximately 60% of the newborn cells that don’t terminally differentiate die within one week of their generation.25 The neurons that survive and mature are thought to be integrated into existing circuitry as functional neurons.26,27 Neurons that do not die within this initial period survive for at least 19 months in rodents.28 Survival of new neurons can be increased by some interventions, such as learning new tasks and environmental enrichment.29,30
A number of factors are involved in the regulation of the process of the birth of new neurons and their subsequent migration, maturation and survival. Neurotransmitters have complex effects on hippocampal neuronal proliferation. Serotoninergic, cholinergic and noradrenergic activation all increase neurogenesis in the dentate gyrus.3133 GABA, acting through GABAA receptors, decreases proliferation in both the dentate gyrus and the SVZ,34,35 and dopaminergic signaling has a similar inhibitory effect.3638 Growth factors also can affect neurogenesis. For example, brain-derived neurotrophic factor (BDNF) enhances hippocampal proliferation, an effect that is blocked by BDNF-specific antibodies.39 Insulin-like growth factor 1 (IGF-1),40 transforming growth factor (TGF), vascular endothelial growth factor (VGEF) and others growth factors have been shown to induce proliferation in the dentate gyrus.4145 The Wnt signaling pathway was identified to induce neurogenesis in the dentate gyrus.46 Corticosteroids were the first hormones found to have an affect on hippocampal neurogenesis.41 Activation of hypothalamic-pituitary-adrenal axis and sustained elevation of glucocorticoids can lead to chronic inhibition of neurogenesis,47 whereas adrenalectomy leads to an increase in the number of neurons in the adult rat hippocampus.48 Thyroid hormones also stimulate neurogenesis.47 Inflammation, which gives rise to microglial activation in the area where the new neurons are born, strongly impairs hippocampal neurogenesis in rodents.49,50 Inflammation does not affect precursor cell proliferation, but it reduces neuronal differentiation and survival, effects likely due to microglia-derived interleukin-6 (IL-6). In contrast, leukemia inhibitory factor (LIF), a cytokine that belongs to the same IL-6 family of cytokines, is induced in the brain in response to brain injury and hypoxia, and increases neuronal proliferation and survival.51 Thus, neurotransmitters, multiple growth factors, hormonal status and pro-inflammatory molecules all can modulate neurogenesis.
The generation of neurons by progenitor cells involves the tight coordination of multiple cellular activities, including exit from the cell cycle, migration and differentiation. During development of the central nervous system, cycling progenitor cells generate post-mitotic neuronal precursors that rapidly migrate out of germinal zones and initiate neuronal differentiation (reviewed in ref. 52). The mechanisms involved in the maintenance of quiescence or the initiation of neuronal cell proliferation remain a central question in developmental biology. In adult mammalian brain, most neuronal cells stay in a quiescent, differentiated state. In post-mitotic, terminally differentiated neurons, it is likely that cell cycle activity is arrested by the increased expression of Cdk inhibitors. Numerous cell cycle inhibitors are expressed in the brain either in a ubiquitous fashion (e.g., p19Ink4d) or in specific regions: p15Ink4d in the forebrain; p21Cip1 in the cerebellum53 and p27Kip1 in the cerebellum and cortical post-mitotic neurons.53,54 In animals derived from backcrosses between p27Kip1-null and p19Ink4d-null mice, a subpopulation of neurons showed increased proliferation in the brain, indicating that these two Cdk inhibitors cooperate to maintain differentiated neurons in a quiescent but potentially reversible state.55
Cell cycle exit and differentiation also has been shown to involve negative cell cycle regulators. In developing olfactory epithelium, there is a temporal progression of the expression of p27Kip1, p18Ink4c, p16Inc4d and p21Cip1 during the transition from neural cell cycle exit to olfactory neuron maturation. Thus, different Cdk inhibitors act sequentially,56 and this non-overlapping pattern suggests that these proteins have independent roles in the brain. In primary adult hippocampal-derived stem cells, exposure to cell cycle exit factors increases p21Cip1 expression.57 In mammal brain, the role of cell cycle related proteins often goes beyond regulation of cell cycle progression. They can act as neuronal differentiation factors, especially during development. 52 Increased expression of p21Cip1 is associated with terminal differentiation in many cell types.58 In PC12 pheochromocytoma cells, a model system to study neuronal differentiation, induction of differentiation leads to p21Cip1 accumulation.59,60 Another Cdk inhibitor p57Kip2 is predominantly expressed in fully differentiated neurons in the SVZ.61 p27Kip1 plays an important role in neurogenesis in the developing mouse cerebral cortex by promoting differentiation and radial migration of cortical projection neurons.62 p27Kip1, paired with Cdk5, controls cytoskeletal changes essential for neuronal migration.63 The Xenopus Cdk inhibitor Xic1 shows homology with mammalian p21Cip1, p27Kip1 and p57Kip2. When stimulated by Notch1, Xic1 promotes neuronal differentiation, and this function is distinct from its ability to inhibit the cell cycle.64
It has been hypothesized that the microenvironments in the SVZ and SGZ, known as the neurogenic niche, might have specific factors necessary for the proliferation and differentiation of neural progenitors and their integration into existing neural networks.65 Cdk inhibitors might control neural progenitor proliferation within neurogenic niches. p27Kip1 regulates the division of transit amplifying progenitors (type 2a cells) in the adult SVZ.66 Loss of p27Kip1 has no effect on the number of NSC, but selectively increases the number of transit-amplifying progenitors concomitantly with a reduction in the number of neuroblasts in the SVZ. Recently, we demonstrated the abundant expression of intranuclear p21Cip1 in the SGZ, where it is colocalized with NeuN, a marker for neurons67 (Fig. 1). DCX is a marker of young neurons. By using FACS analysis we found that among DCX-positive cells, 42.8% stained positive for p21Cip1, indicating that p21Cip1 is expressed in newly developing neurons (type 2b cells). p21Cip1-null mice were examined, and the rate of cellular proliferation was increased in the SGZ of p21Cip1-deficient mice compared with wild-type animals. In addition, the levels of both DCX and NeuN protein were increased in adult p21Cip1-null mice, further demonstrating increased hippocampal neuronal proliferation. Surprisingly, p21Cip1 was not expressed in terminally differentiated granular neurons in the dentate gyrus (Fig. 1). Others have found that brain ischemia produces a greater activation of neuronal proliferation in the SGZ and SVZ of p21Cip1-null mice compared to wild-type mice,68 indicating that cell cycle activation of neuronal precursors is intrinsically inhibited by p21Cip1. Based upon these data, we speculate that p21Cip1 expressed in the SGZ is a part of the hippocampal neurogenic niche, and has an important role in regulating the number of newly developing neurons in this region. Cell-specific properties of cell cycle regulators have been described. For example, RB induces the p21Cip1 promoter in epithelial cells, but not in fibroblasts.69 Pituitary tumor-transforming gene (PTTG) deletion resulted in p21Cip1 induction in the pituitary, but not in the thyroid, thymus or spleen.70 Thus, p21Cip1 protein might play specific role in hippocampal neurogenesis in the SGZ.
Figure 1
Figure 1
p21Cip1 is expressed in the SGZ of the dentate gyrus of the hippocampus. The confocal image shows intra-nuclear expression of p21 as demonstrated by co-localization of neurons (NeuN, green), DNA (blue) and p21Cip1 (red). Cell where p21Cip1 is expressed (more ...)
Neurogenesis declines with aging in both SVZ and SGZ.71 In rodents, the decline in SGZ neurogenesis mainly occurs between 2 and 12 months of age,3 and control of cell division and death is critical in this process. Progenitor proliferation in the SVZ, neurogenesis in OB as well as multipotent progenitor frequency and self-renewal potentials all decline with age.72 This is associated with increased expression of the Cdk inhibitor p16Ik4a, a protein that has been linked to cellular senescence. Aging p16Ink4a-null mice have smaller declines in SVZ proliferation and multipotent progenitor frequency and self-renewal potentials. Interestingly, p16Ink4a deficiency does not affect progenitor function in the SGZ, indicating regional differences during aging.72 In mice overexpressing the short (truncated) form of p53 (p44 mice),73 the interaction between the full-length and short isoforms of p53 stabilizes p53 function and increases transcription of p21Cip1. This increase in p21Cip1 expression is associated with a diminished capacity for neurogenesis. As these mice age they undergo a more pronounced decrease in neuronal proliferation in the SVZ, a reduced number of neurons in the OB, and exhibit features of premature aging.74 Thus, the progressive loss of neurogenesis might involve age-related changes in the regulation of cell cycle inhibitors.
The functional significance of adult neurogenesis is not known. The hippocampus is involved in a number of important functions, including memory formation and retrival, learning, and neuroendocrine and mood regulation. Many studies have attempted to link changes in hippocampal neurogenesis to alterations or deficits in these endpoints. The relationships among hippocampal neurogenesis, depression and the mechanism of action of antidepressant drugs have generated a considerable amount of interest and controversy. This has led to a neurogenesis theory of depression (or antidepressant action). In rodents, chronic stress (or glucocorticoid administration) induces “depression-like” behavior, and this is accompanied by decreased hippocampal neurogenesis.75,76 In humans, stress has been found to play one of the leading roles in the pathogenesis of depression.77,78 Chronic stress (or glucocorticoid administration) leads to hippocampal atrophy in rodents, and in humans, depression is associated with hippocampal atrophy.75,76 However, it is improbable that depression-related decreases in hippocampal neurogenesis could produce a sufficient reduction in hippocampal volume that it could be detected using imaging. Major depression is associated with neurocognitive deficits and neuroendocrine dysregulation, both of which could involve impairment of hippocampal function.
If depression is due to decreased hippocampal neurogenesis, then reducing neurogenesis should produce depression. This has not been found to be the case because reducing hippocampal neurogenesis does not produce depression-like behavior in animals models, although it has been argued that this is due to the lack of appropriate and valid animal models of human depression. A seminal study reported that radiation-induced inhibition of hippocampal neurogenesis blocked the behavioral effects of a tricyclic and a SSRI antidepressant.79 However, this study was criticized because the behavioral test used might have been sensitive to the anxiolytic properties of the drugs and was not appropriate for the detection of antidepressant activity, and the selectivity of the radiation-induced lesion was problematic.
One of the most compelling lines of evidence linking depression and neurogenesis are the findings that antidepressant drugs, and procedures and tasks that reduce depression, such as electroconvulsive shock78,8082 and exercise,83 increase neurogenesis. Most antidepressant drugs produce a rapid increase in extracellular levels of norepinephrine and/or serotonin; however, the onset of appreciable clinical improvement usually takes 3–4 weeks.84 This delay suggests that long-term adaptation in neurotransmitter systems and/or their downstream targets might be necessary for their therapeutic effects.
Antidepressants increase neurogenesis in the adult hippocampus.80,85 They appear to increase the proliferation rate of neuronal progenitors without affecting the rate of survival or the rate of differentiation into neurons.86 The induction of neurogenesis requires repeated treatment with the antidepressant, and the time course of neurogenesis is consistent with time course of its therapeutic effects.48 Upregulation of neurogenesis occurs after the chronic administration of different classes of antidepressants, including tricyclic antidepressants, selective serotonin (SSRI) and norepinephrine (SNRI) reuptake inhibitors and monoamine oxidase inhibitors.80,85 Some drugs that do not directly affect biogenic amine reuptake also stimulate neurogenesis and have antidepressant activity. For example, agomelatine, a new antidepressant that acts as a melatonin agonist, also stimulates neurogenesis in rat hippocampus,87 as do thyroid hormones, which have been used in the treatment of depression.47 Psychotropic drugs that do not have antidepressant activity, such as haloperidol, have no effect on neurogenesis.85 Thus, the induction of adult neurogenesis might represent a common final target for different classes of antidepressants. Determining how antidepressant drugs stimulate neurogenesis remains an interesting and thought-provoking area of research.
Although it is well established that antidepressant therapies stimulate neuronal proliferation, very limited data are available on the fundamental mechanisms underlying this effect. It recently was shown that VEGF signaling through a high affinity receptor tyrosine kinase (Flk-1) is necessary and sufficient for the both the neurogenic and behavioral actions of multiple classes of antidepressants88 The signaling pathway by which antidepressants induce VEGF expression could involve the cAMP response element binding protein (CREB).80,89 There is evidence that antidepressant treatment might affect neuronal progenitor cells. Thus, the selective serotonin re-uptake inhibitor fluoxetine does not affect the division of stem-cell like cells, but increases the division of early neuronal progenitors.23
In our experiments, chronic treatment with the tricyclic antidepressant imipramine stimulated neurogenesis in the hippocampus. This imipramine-induced increase in the number of SGZ neurons was associated with markedly decreased hippocampal p21Cip1 mRNA and protein levels, concordant with an increased number of mature neurons expressing NeuN.67 These results suggest that p21Cip1 restrains neurogenesis in the SGZ, and the imipramine-induced stimulation of neurogenesis might be a consequence of decreased p21Cip1 expression and the subsequent release of neuronal progenitor cells from the blockade of proliferation. These data were the first to show that proteins involved in the regulation of the cell cycle are a possible mechanistic link between neurogenesis and action of antidepressants. The signaling cascade underlying imipramine-induced suppression of p21Cip1 is not known. Imipramine inhibits the reuptake of both norepinephrine and serotonin, and it is likely that imipramine suppresses p21Cip1 promoter activity secondary to its effects on one or both neurotransmitters. Local hippocampal factors also could be involved in the regulation of p21Cip1 expression. For example, the interplay between transforming growth factor beta-2 (TGFβ2) and brain-derived neurotrophic factor in the cerebellum has been suggested to account for anti-proliferative and pro-differentiating activities observed in post-mitotic cerebellar neurons.90 Because many antidepressants stimulate neurogenesis, it is possible that their shared common mechanism of action is suppression of p21Cip1. Importantly, these studies indicate that processes regulating cell cycle progression are operable in the adult brain and therefore may potentially be a target for therapy.
The discovery of adult neurogenesis raised expectations for improved treatments for patients with central nervous system disorders. Despite all of the controversy surrounding the role of neurogenesis in etiology of depression, the consensus opinion is that increased neurogenesis triggered by antidepressants in some manner contributes to their therapeutic effects. It is possible that new therapeutic strategies for the treatment of depression could involve stimulating neurogenesis by targeting cell cycle related proteins. The new findings with regards to antidepressants and neurogenesis have a number of interesting ramifications. For example, it has been suggested that more neurogenesis is not necessarily beneficial.30 Increased mitotic expansion without corresponding increases in the rate of differentiation could lead to a large pool of undifferentiated cells, which could have adverse consequences. Excessive neurogenesis also could result in inappropriate migration, differentiation and integration into existing neural networks, and could underlie such pathological conditions as epilepsy.30
The studies of the effects of antidepressants on neurogenesis have focused on relatively short-term antidepressant administration (i.e., 28 days or less). Constant and/or long-term stimulation of neurogenesis by antidepressant treatment might have adverse consequences. Relative quiescence might extend stem cell longevity (long-term maintenance of self-renewal ability) by preventing the exhaustion of the capacity to proliferate.91,92 It was shown that NSC have finite proliferation potentials and p21Cip1 negatively regulates adult NSC proliferation.93,94 We found that treatment with antidepressant for three weeks suppresses murine SGZ p21Cip1 expression with a subsequent increase in hippocampal neurogenesis.67 Therefore it is conceivable that suppression of p21Cip1 by longer treatment could result in eventual and premature exhaustion of neuronal precursors as it was observed in aging p21Cip1-null mice.93 If this is the case, then in some instances it could lead to the loss of therapeutic efficacy, or the development of treatment refractory depression, and this appears to be true. A relatively common and troubling phenomenon is that antidepressant drugs, especially SSRIs, loose their effectiveness after long-term use.95 This has been called relapse during maintenance treatment (in common terms, “Prozac poop-out”). A possible mechanism underling this effect is exhaustion of neurogenesis due to excessive stimulation.
The role of neurogenesis in normal and diseased states is not known, but it has been hypothesized to be involved in neuronal plasticity underlying emotional states, memory and cognition. It has been reported that neurocognitive deficits can be observed in patients undergoing long-term antidepressant treatment even though their mood disorder is well controlled by the drug.96 One study found moderate changes in memory and cognitive function in patients with major depression after an average of 2 years of treatment with different classes of antidepressants.97 The extent to which these deficits in cognitive function are due to the underlying depressive disorder or antidepressant treatment are not known, but it is possible that long-term antidepressant therapy might affect cognitive function by disrupting the normal regulation of neurogensis. This might be more significant in elderly patients, who also have age-related deficits in cognitive function. It is interesting to note that depression is very common in the elderly, who conceivably have a reduced rate of hippocampal neurogenesis. It is possible that neurogenesis-dependent effects of antidepressants might be decreased in this population.
Antidepressants are commonly prescribed drugs that undoubtedly are effective in treating mood disorders. They are widely used not only in adults, but also in children and adolescents. The rate of antidepressant drug treatment has increased more than four times between early 1990s and early 2000s.98 We are beginning to learn more and more about the effects of antidepressants on neuronal function. The finding that antidepressants affect cell cycle proteins opens up new avenues for research and drug development. However, with this new information comes the possibility that some the adverse effects produced by antidepressants and the limitations of drug therapy might involve interactions with cell cycle regulatory proteins.
Acknowledgements
This work was partially support by a NARSAD Young Investigator Award (V.C), National Institutes of Health Grants MH079988 (V.C), MH078037 (R.N.P.) and MH079370 (R.N.P.), and the Levine Family Fund Research Endowment (R.N.P.).
1. Altman J. Are new neurons formed in the brains of adult mammals? Science. 1962;135:1127–1128. [PubMed]
2. Nowakowski RS, Lewin SB, Miller MW. Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population. J Neurocytol. 1989;18:311–318. [PubMed]
3. Abrous DN, Koehl M, Le Moal M. Adult neurogenesis: from precursors to network and physiology. Physiol Rev. 2005;85:523–569. [PubMed]
4. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132:645–660. [PubMed]
5. Elder GA, De Gasperi R, Gama Sosa MA. Research update: neurogenesis in adult brain and neuropsychiatric disorders. Mt Sinai J Med. 2006;73:931–940. [PubMed]
6. Gould E. How widespread is adult neurogenesis in mammals? Nat Rev Neurosci. 2007;8:481–488. [PubMed]
7. Amrein I, Slomianka L, Poletaeva II, Bologova NV, Lipp HP. Marked species and age-dependent differences in cell proliferation and neurogenesis in the hippocampus of wild-living rodents. Hippocampus. 2004;14:1000–1010. [PubMed]
8. Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996;16:2027–2033. [PubMed]
9. Rao MS, Hattiangady B, Shetty AK. The window and mechanisms of major age-related decline in the production of new neurons within the dentate gyrus of the hippocampus. Aging Cell. 2006;5:545–558. [PubMed]
10. He J, Crews FT. Neurogenesis decreases during brain maturation from adolescence to adulthood. Pharmacol Biochem Behav. 2007;86:327–333. [PubMed]
11. Gage FH. Mammalian neural stem cells. Science. 2000;287:1433–1438. [PubMed]
12. Rakic P. Neurogenesis in adult primates. Prog Brain Res. 2002;138:3–14. [PubMed]
13. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313–1317. [PubMed]
14. Curtis MA, Eriksson PS, Faull RL. Progenitor cells and adult neurogenesis in neurodegenerative diseases and injuries of the basal ganglia. Clin Exp Pharmacol Physiol. 2007;34:528–532. [PubMed]
15. Rakic P. Neurogenesis in adult primate neocortex: an evaluation of the evidence. Nat Rev Neurosci. 2002;3:65–71. [PubMed]
16. Bhardwaj RD, Curtis MA, Spalding KL, Buchholz BA, Fink D, Bjork-Eriksson T, Nordborg C, Gage FH, Druid H, Eriksson PS, Frisen J. Neocortical neurogenesis in humans is restricted to development. Proc Natl Acad Sci USA. 2006;103:12564–12568. [PubMed]
17. Rakic P. Neuroscience. No more cortical neurons for you. Science. 2006;313:928–929. [PubMed]
18. Fukuda S, Kato F, Tozuka Y, Yamaguchi M, Miyamoto Y, Hisatsune T. Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus. J Neurosci. 2003;23:9357–9366. [PubMed]
19. Mignone JL, Kukekov V, Chiang AS, Steindler D, Enikolopov G. Neural stem and progenitor cells in nestin-GFP transgenic mice. J Comp Neurol. 2004;469:311–324. [PubMed]
20. Kunze A, Grass S, Witte OW, Yamaguchi M, Kempermann G, Redecker C. Proliferative response of distinct hippocampal progenitor cell populations after cortical infarcts in the adult brain. Neurobiol Dis. 2006;21:324–332. [PubMed]
21. Miles DK, Kernie SG. Hypoxic-ischemic brain injury activates early hippocampal stem/progenitor cells to replace vulnerable neuroblasts. Hippocampus. 2008 [PubMed]
22. Seri B, Garcia-Verdugo JM, Collado-Morente L, McEwen BS, Alvarez-Buylla A. Cell types, lineage and architecture of the germinal zone in the adult dentate gyrus. J Comp Neurol. 2004;478:359–378. [PubMed]
23. Encinas JM, Vaahtokari A, Enikolopov G. Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci USA. 2006;103:8233–8238. [PubMed]
24. Kronenberg G, Reuter K, Steiner B, Brandt MD, Jessberger S, Yamaguchi M, Kempermann G. Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. J Comp Neurol. 2003;467:455–463. [PubMed]
25. Dayer AG, Ford AA, Cleaver KM, Yassaee M, Cameron HA. Short-term and long-term survival of new neurons in the rat dentate gyrus. J Comp Neurol. 2003;460:563–572. [PubMed]
26. van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature. 2002;415:1030–1034. [PubMed]
27. Zhao C, Teng EM, Summers RG, Jr, Ming GL, Gage FH. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci. 2006;26:3–11. [PubMed]
28. Winner B, Cooper-Kuhn CM, Aigner R, Winkler J, Kuhn HG. Long-term survival and cell death of newly generated neurons in the adult rat olfactory bulb. Eur J Neurosci. 2002;16:1681–1689. [PubMed]
29. Kempermann G, Gast D, Kronenberg G, Yamaguchi M, Gage FH. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development. 2003;130:391–399. [PubMed]
30. Scharfman HE, Hen R. Neuroscience. Is more neurogenesis always better? Science. 2007;315:336–338. [PMC free article] [PubMed]
31. Brezun JM, Daszuta A. Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience. 1999;89:999–1002. [PubMed]
32. Cooper-Kuhn CM, Winkler J, Kuhn HG. Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J Neurosci Res. 2004;77:155–165. [PubMed]
33. Mohapel P, Leanza G, Kokaia M, Lindvall O. Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging. 2005;26:939–946. [PubMed]
34. Tozuka Y, Fukuda S, Namba T, Seki T, Hisatsune T. GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron. 2005;47:803–815. [PubMed]
35. Liu X, Wang Q, Haydar TF, Bordey A. Nonsynaptic GABA signaling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors. Nat Neurosci. 2005;8:1179–1187. [PMC free article] [PubMed]
36. Dawirs RR, Hildebrandt K, Teuchert-Noodt G. Adult treatment with haloperidol increases dentate granule cell proliferation in the gerbil hippocampus. J Neural Transm. 1998;105:317–327. [PubMed]
37. Yamaguchi M, Suzuki T, Seki T, Namba T, Juan R, Arai H, Hori T, Asada T. Repetitive cocaine administration decreases neurogenesis in adult rat hippocampus. Ann N Y Acad Sci. 2004;1025:351–362. [PubMed]
38. Kippin TE, Kapur S, van der Kooy D. Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci. 2005;25:5815–5823. [PubMed]
39. Katoh-Semba R, Asano T, Ueda H, Morishita R, Takeuchi IK, Inaguma Y, Kato K. Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. Faseb J. 2002;16:1328–1330. [PubMed]
40. Aberg MA, Aberg ND, Palmer TD, Alborn AM, Carlsson-Skwirut C, Bang P, Rosengren LE, Olsson T, Gage FH, Eriksson PS. IGF-I has a direct proliferative effect in adult hippocampal progenitor cells. Mol Cell Neurosci. 2003;24:23–40. [PubMed]
41. Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci. 2006;7:179–193. [PubMed]
42. Emsley JG, Hagg T. Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice. Exp Neurol. 2003;183:298–310. [PubMed]
43. Jin K, Sun Y, Xie L, Batteur S, Mao XO, Smelick C, Logvinova A, Greenberg DA. Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Aging Cell. 2003;2:175–183. [PubMed]
44. Jin K, Xie L, Childs J, Sun Y, Mao XO, Logvinova A, Greenberg DA. Cerebral neurogenesis is induced by intranasal administration of growth factors. Ann Neurol. 2003;53:405–409. [PubMed]
45. Kuhn HG, Winkler J, Kempermann G, Thal LJ, Gage FH. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J Neurosci. 1997;17:5820–5829. [PubMed]
46. Song H, Stevens CF, Gage FH. Astroglia induce neurogenesis from adult neural stem cells. Nature. 2002;417:39–44. [PubMed]
47. Montero-Pedrazuela A, Venero C, Lavado-Autric R, Fernandez-Lamo I, Garcia-Verdugo JM, Bernal J, Guadano-Ferraz A. Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior. Mol Psychiatry. 2006;11:361–371. [PubMed]
48. Wong EY, Herbert J. Raised circulating corticosterone inhibits neuronal differentiation of progenitor cells in the adult hippocampus. Neuroscience. 2006;137:83–92. [PMC free article] [PubMed]
49. Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA. 2003;100:13632–13637. [PubMed]
50. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760–1765. [PubMed]
51. Bauer S, Kerr BJ, Patterson PH. The neuropoietic cytokine family in development, plasticity, disease and injury. Nat Rev Neurosci. 2007;8:221–232. [PubMed]
52. Ohnuma S, Philpott A, Harris WA. Cell cycle and cell fate in the nervous system. Curr Opin Neurobiol. 2001;11:66–73. [PubMed]
53. Legrier ME, Ducray A, Propper A, Kastner A. Region-specific expression of cell cycle inhibitors in the adult brain. Neuroreport. 2001;12:3127–3131. [PubMed]
54. Yoshikawa K. Cell cycle regulators in neural stem cells and postmitotic neurons. Neurosci Res. 2000;37:1–14. [PubMed]
55. Zindy F, Soares H, Herzog KH, Morgan J, Sherr CJ, Roussel MF. Expression of INK4 inhibitors of cyclin D-dependent kinases during mouse brain development. Cell Growth Differ. 1997;8:1139–1150. [PubMed]
56. Legrier ME, Ducray A, Propper A, Chao M, Kastner A. Cell cycle regulation during mouse olfactory neurogenesis. Cell Growth Differ. 2001;12:591–601. [PubMed]
57. Takahashi J, Palmer TD, Gage FH. Retinoic acid and neurotrophins collaborate to regulate neurogenesis in adult-derived neural stem cell cultures. J Neurobiol. 1999;38:65–81. [PubMed]
58. Gartel AL, Tyner AL. The growth-regulatory role of p21 (WAF1/CIP1) Prog Mol Subcell Biol. 1998;20:43–71. [PubMed]
59. Perez-Juste G, Aranda A. The cyclin-dependent kinase inhibitor p27(Kip1) is involved in thyroid hormone-mediated neuronal differentiation. J Biol Chem. 1999;274:5026–5031. [PubMed]
60. Tikoo R, Casaccia-Bonnefil P, Chao MV, Koff A. Changes in cyclin-dependent kinase 2 and p27kip1 accompany glial cell differentiation of central glia-4 cells. J Biol Chem. 1997;272:442–447. [PubMed]
61. van Lookeren Campagne M, Gill R. Tumor-suppressor p53 is expressed in proliferating and newly formed neurons of the embryonic and postnatal rat brain: comparison with expression of the cell cycle regulators p21Waf1/Cip1, p27Kip1, p57Kip2, p16Ink4a, cyclin G1, and the proto-oncogene Bax. J Comp Neurol. 1998;397:181–198. [PubMed]
62. Nguyen L, Besson A, Heng JI, Schuurmans C, Teboul L, Parras C, Philpott A, Roberts JM, Guillemot F. p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes Dev. 2006;20:1511–1524. [PubMed]
63. Kawauchi T, Chihama K, Nabeshima Y, Hoshino M. Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nat Cell Biol. 2006;8:17–26. [PubMed]
64. Vernon AE, Movassagh M, Horan I, Wise H, Ohnuma S, Philpott A. Notch targets the Cdk inhibitor Xic1 to regulate differentiation but not the cell cycle in neurons. EMBO Rep. 2006;7:643–648. [PubMed]
65. Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell. 2008;132:598–611. [PubMed]
66. Doetsch F. The glial identity of neural stem cells. Nat Neurosci. 2003;6:1127–1134. [PubMed]
67. Pechnick RN, Zonis S, Wawrowsky K, Pourmorady J, Chesnokova V. p21Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus. Proc Natl Acad Sci USA. 2008;105:1358–1363. [PubMed]
68. Qiu J, Takagi Y, Harada J, Rodrigues N, Moskowitz MA, Scadden DT, Cheng T. Regenerative response in ischemic brain restricted by p21cip1/waf1. J Exp Med. 2004;199:937–945. [PMC free article] [PubMed]
69. Decesse JT, Medjkane S, Datto MB, Cremisi CE. RB regulates transcription of the p21/WAF1/CIP1 gene. Oncogene. 2001;20:962–971. [PubMed]
70. Chesnokova V, Zonis S, Rubinek T, Yu R, Ben-Shlomo A, Kovacs K, Wawrowsky K, Melmed S. Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth. Cancer Res. 2007;67:10564–10572. [PMC free article] [PubMed]
71. Rossi DJ, Jamieson CH, Weissman IL. Stems cells and the pathways to aging and cancer. Cell. 2008;132:681–696. [PubMed]
72. Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature. 2006;443:448–452. [PMC free article] [PubMed]
73. Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 2004;18:306–319. [PubMed]
74. Medrano S, Scrable H. Maintaining appearances—the role of p53 in adult neurogenesis. Biochem Biophys Res Commun. 2005;331:828–833. [PubMed]
75. Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, Bartolomucci A, Fuchs E. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci USA. 2001;98:12796–12801. [PubMed]
76. McEwen BS, Tanapat P, Weiland NG. Inhibition of dendritic spine induction on hippocampal CA1 pyramidal neurons by a nonsteroidal estrogen antagonist in female rats. Endocrinology. 1999;140:1044–1047. [PubMed]
77. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci. 1997;17:2492–2498. [PubMed]
78. Warner-Schmidt JL, Duman RS. Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus. 2006;16:239–249. [PubMed]
79. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–809. [PubMed]
80. Duman RS. Depression: a case of neuronal life and death? Biol Psychiatry. 2004;56:140–145. [PubMed]
81. Malberg JE, Blendy JA. Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci. 2005;26:631–638. [PubMed]
82. Perera TD, Coplan JD, Lisanby SH, Lipira CM, Arif M, Carpio C, Spitzer G, Santarelli L, Scharf B, Hen R, Rosoklija G, Sackeim HA, Dwork AJ. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J Neurosci. 2007;27:4894–4901. [PubMed]
83. Fabel K, Kempermann G. Physical Activity and the Regulation of Neurogenesis in the Adult and Aging Brain. Neuromolecular Med. 2008 [PubMed]
84. Frazer A, Benmansour S. Delayed pharmacological effects of antidepressants. Mol Psychiatry. 2002;7:23–28. [PubMed]
85. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104–9110. [PubMed]
86. Malberg JE. Implications of adult hippocampal neurogenesis in antidepressant action. J Psychiatry Neurosci. 2004;29:196–205. [PMC free article] [PubMed]
87. Banasr M, Soumier A, Hery M, Mocaer E, Daszuta A. Agomelatine, a New Antidepressant, Induces Regional Changes in Hippocampal Neurogenesis. Biol Psychiatry. 2006 [PubMed]
88. Warner-Schmidt JL, Duman RS. VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci USA. 2007;104:4647–4652. [PubMed]
89. Impey S, McCorkle SR, Cha-Molstad H, Dwyer JM, Yochum GS, Boss JM, McWeeney S, Dunn JJ, Mandel G, Goodman RH. Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell. 2004;119:1041–1054. [PubMed]
90. Lu J, Wu Y, Sousa N, Almeida OF. SMAD pathway mediation of BDNF and TGFbeta2 regulation of proliferation and differentiation of hippocampal granule neurons. Development. 2005;132:3231–3242. [PubMed]
91. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993;81:2844–2853. [PubMed]
92. Weiss S, van der Kooy D. CNS stem cells: where’s the biology (a.k.a. beef)? J Neurobiol. 1998;36:307–314. [PubMed]
93. Kippin TE, Martens DJ, van der Kooy D. p21 loss compromises the relative quiescence of forebrain stem cell proliferation leading to exhaustion of their proliferation capacity. Genes Dev. 2005;19:756–767. [PubMed]
94. Meletis K, Wirta V, Hede SM, Nister M, Lundeberg J, Frisen J. p53 suppresses the self-renewal of adult neural stem cells. Development. 2006;133:363–369. [PubMed]
95. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, Niederehe G, Thase ME, Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF, Sackeim HA, Kupfer DJ, Luther J, Fava M. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–1917. [PubMed]
96. Fava M. Symptoms of fatigue and cognitive/executive dysfunction in major depressive disorder before and after antidepressant treatment. J Clin Psychiatry. 2003;64:30–34. [PubMed]
97. Gorenstein C, de Carvalho SC, Artes R, Moreno RA, Marcourakis T. Cognitive performance in depressed patients after chronic use of antidepressants. Psychopharmacology (Berl) 2006;185:84–92. [PubMed]
98. Mojtabai R. Increase in antidepressant medication in the US adult population between 1990 and 2003. Psychother Psychosom. 2008;77:83–89. [PubMed]