Philippe Taupin.indd Drug Target Insights 2006: 1 13–17 13 Correspondence: 11 Jalan Tan Tock Seng, Singapore 308433. Tel: (65) 6357-7533; Fax: (65) 6256-9178; Email: obgpjt@nus.edu.sg Please note that this article may not be used for commercial purposes. For further information please refer to the copyright statement at http://www.la-press.com/copyright.htm REVIEW Neurogenesis and The Effect of Antidepressants Philippe Taupin1,2,3 1National Neuroscience Institute, Singapore. 2National University of Singapore. 3Nanyang Technological University, Singapore. Abstract: The recent evidence that neurogenesis occurs throughout adulthood and neural stem cells (NSCs) reside in the adult central nervous system (CNS) suggests that the CNS has the potential for self-repair. Beside this potential, the function of newly generated neuronal cells in the adult brain remains the focus of intense research. The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests that adult neurogenesis may contribute to the biology of depression. The observations that antidepressants, like fl uoxetine, increase neurogenesis in the dentate gyrus (DG) and neurogenesis is required for the behavioral effect of antidepressants, lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression. However, the role of adult neurogenesis in the etiology of depres- sion remains the source of controversies and debates. Keywords: neural stem cells, hippocampus, depression, fl uoxetine, cellular therapy. Introduction Neurogenesis, the generation of new neuronal cells, occurs in the adult brain of mammals (Gage, 2000; Gross, 2000), including human (Eriksson et al. 1998). Neurogenesis occurs primarily in two regions of the adult brain: the DG and the subventricular zone (SVZ) (Taupin and Gage, 2001). Newly generated neuronal cells establish synaptic and functional connections with nerve cells of the pre-existing network (Stanfi eld and Trice, 1988; Markakis and Gage, 1999; van Praag et al. 2002). It is hypothesized that newborn neuronal cells arise from stem cells in the adult brain. NSCs are the self-renewing multipotent cells that generate the main phenotypes of the nervous system, neurons, astrocytes and oligodendrocytes; as such they hold the potential to treat a broad range of CNS diseases and injuries (Mckay, 1997). Neural progenitor and stem cells have been isolated and characterized in vitro from the adult brain, further supporting the existence of NSCs in the adult CNS (Reynolds and Weiss, 1992; Gage et al. 1995). The existence of NSCs in the adult brain has tremendous consequences for cellular therapy in the CNS, but also for our understanding of developmental biology (Taupin, 2006a). Depression is a major public health problem that affects 12–17% of the population (Kessler et al. 1994). Various classes of drugs are currently prescribed for the treatment of depression (Wong and Licinio, 2001; Brunello et al. 2002). Among them selective serotonin reuptake inhibitors (SSRIs), like fl uoxetine, monoamine oxidase inhibitors (MAOIs), like tranylcypromine, specifi c norepinephrine reuptake inhibitors (SNRIs), like reboxetine and phosphodiesterase-IV inhibitors, like rolipram, alleviate symptoms of depression. It is hypothesized that an imbalance in serotonin (5-hydroxytryptamine or 5-HT) and noradrenaline (NA) pathways may underlie the pathogenesis of depressive disorders (Hind- march, 2001; Owens, 2004). SSRIs, like fl uoxetine, may produce their therapeutic effects by increasing brain levels of 5-HT, a neurotransmitter implicated in the modulation of mood and anxiety-related disorders (Whittington et al. 2004; Ryan, 2005). Among the 5-HT receptor subtypes, the 5-HT1A receptor has been prominently implicated in the modulation of mood and anxiety-related disorders (Gross et al. 2002). There are increasing evidences that the hippocampus, a structure classically involved in leaning and memory, is involved in the modulation of emotional responses, particularly depression. Clinical magnetic resonance imaging and post-mortem studies in depression patients, as well as in animal studies, reveal that chronic stress and depression result in loss of nerve cells and atrophy in the hippocampus, and that these effects can be reversed by antidepressants (Watanabe et al. 1992a; Sheline et al. 1996; Czeh et al. 2001; Campbell et al. 2004; Videbech and Ravnkilde, 2004; Colla et al. 2006). Drug Target Insights 2006: 114 Philippe Taupin This suggests that neurogenesis may be an under- lying factor in the contribution of the hippocampus to depression. In support of this contention, gluco- corticoids, stress-related hormones, induce brain atrophy (Sapolsky, 2000; McEwen, 2001) and decrease neurogenesis (Gould et al. 1991; Cameron and Gould, 1994), whereas antidepressants, like fl uoxetine, promote neurogenesis (Malberg et al. 2000; Malberg and Duman, 2003). Investigators have aimed at confirming and unraveling the mechanism underlying the involvement of adult neurogenesis to the etiology of depression. Neurogenesis Contributes to the Therapeutic Effects of Antidepressants The effect of antidepressants, like fl uoxetine, tran- ylcypromine, reboxetine and rolipram, on adult neurogenesis was assessed by means of bromode- oxyuridine (BrdU) labeling, immunohistochemistry for neuronal specifi c markers and confocal micros- copy (Malberg et al. 2000, 2004). BrdU is a thymi- dine analog that incorporates into the DNA of dividing cells and is used for birthdating cells and monitoring cell proliferation (Miller and Nowa- kowski, 1988; Kuhn et al. 1996; Taupin, 2006b). Chronic administration of these antidepressants increases neurogenesis in the DG, but not the SVZ in adult rats, suggesting that hippocampal neuro- genesis contributes to the therapeutic effects of antidepressants (Malberg et al. 2000, 2004). To study the functional implication of such observations, Santarelli et al. (2003) aimed at characterizing whether an increase in neurogenesis is required for the effect of antidepressants. X-ray irradiation of the hippocampal area in adult rats causes long-term reductions in cell prolifera- tion in the DG (Tada et al. 2000). Hippocampal x-ray irradiation, but not irradiation of other brain areas, like the SVZ or the cerebellar region, prevented the neurogenic effect of antidepressants, like fl uoxetine, in adult mice (Santarelli et al. 2003). The behavioral effect of the antidepressants on the novelty-suppressed feeding (NSF) test was also abolished after hippocampal irradiation. The NSF test, in which animals are food deprived, then placed into a novel environment containing food, and assessed for the latency to begin eating, is devised to assess chronic antidepressant effi cacy in rodents (Bodnoff et al. 1988). Further, 5-HT1A receptor null mice were insensitive to the neurogenic and behavioral effects of fl uoxetine. In all, these data show that SSRIs, like fl uoxetine, increase hippocampal neurogenesis, which contrib- utes to their behavioral effects (Santarelli et al. 2003). A Neurogenic Theory of Depression Stress, an environmental factor, is an important causal factor in precipitating episodes of depres- sion in human, and potently suppresses hippo- campal neurogenesis in adult monkey (Gould et al. 1998; Malberg and Duman, 2003), probably due to increased glucocorticoid release (Gould et al. 1991; Cameron and Gould, 1994). Neuro- genesis plays an important role in biology of depression; particularly the stimulation of neuro- genesis by antidepressants contributes to their behavioral effects (Malberg et al. 2000; Santarelli et al. 2003). It is proposed that stress-induced decrease of neurogenesis in the DG is an important causal factor in precipitating episodes of depres- sion. The waning and waxing of neurogenesis in the hippocampal formation are therefore important causal factors, respectively, in the precipitation of, and recovery from, episodes of clinical depression, probably mediated through the increase in brain serotonin levels (Jacobs et al. 2000). The mechanism underlying the increased neuro- genesis mediated by antidepressants remains to be identifi ed. Studies reveal that the 5-HT, particularly 5-HT1A, receptor subtypes mediate the involve- ment of adult neurogenesis in depression (Banasr et al. 2004), and that fl uoxetine targets a population of early progenitor cells in the DG, rather than stem-like cells in the DG (Encinas et al. 2006). The effect of antidepressants on neurogenesis may be mediated by trophic factors, like brain-derived neurotrophic factor (BDNF). On the one hand, antidepressant treatments increase the level of expression of BDNF in the patents’ brain, and BDNF has an antidepressant effect (Siuciak et al. 1997; Chen et al. 2001; Saarelainen et al. 2003). On the other hand, administration of BDNF increases adult neurogenesis in the hippocampus (Scharfman et al. 2005). This suggests that the effect of antide- pressants on neurogenesis may be mediated by BDNF, through its signaling pathway, particularly the mitogen-activated protein (MAP) kinase pathway (Duman et al. 2006). The MAP kinase pathway is a BDNF signaling cascade mediated Drug Target Insights 2006: 1 15 Neurogenesis and Depression by the activation of MAP kinase (MAPK) that phosphorylates and activates the extracellular signal-regulated kinase (ERK) pathway (Huang and Reichardt, 2003). A hypothesis supported by recent fi ndings showing that exercise promotes hippocampal neurogenesis, BDNF expression, and has an antidepressant effect (van Praag et al. 1999; Eadie et al. 2005; Russo-Neustadt and Chen, 2005; Bjornebekk et al. 2005; Ernst et al. 2006). Though these studies provide compelling evidences of the role of BDNF in depression and neurogenesis, it remains to link the activity of BDNF on the increase of neurogenesis mediated by antidepressants. There are however controversies and debates over the involvement of the hippocampus and adult neurogenesis in the etiology of depression. Among them, i) a link between neurogenesis, loss of nerve cells, atrophy and decrease of hippocampal volume in depression subjects is yet to be demonstrated, ii) studies show that hippocampal volume remains unchanged in depressive patients (Axelson et al. 1991; Inagaki et al. 2004; Bielau et al. 2005), iii) the hippocampal formation may not be primarily involved in depressive episodes, as other areas of the brain may play a critical role in depression (Nestler et al. 2002; Ebmeier et al. 2006), iv) there are questions over validity of animal models of depression as representative of the human disorder, and v) neurogenesis may be more a contributing factor of CNS plasticity, rather than to specific physiological or pathological processes (Taupin, 2006c). The involvement of adult neurogenesis in depression remains therefore speculative (Feldmann et al. 2006). In all these data involved the hippocampus, a structure classically involved in leaning and memory, and adult neurogenesis in depression and anxiety disorders (Thomas and Peterson, 2003). Antidepressant treatments may increase neural plasticity and adult neurogenesis, especially in the hippocampus. However, the neurogenic theory of depression remains the source of debates and controversies, and to be further confi rmed (Feld- mann et al. 2006). More data and evidences are needed to confi rm the involvement of adult neuro- genesis in depression. Conclusion These studies show that antidepressants increase hippocampal neurogenesis, and establish a causal relation between the stimulation of neurogenesis and the effect of antidepressants. New neuronal cells that survived and integrate the pre-existing network survive for long period, over two years in human (Eriksson et al. 1998). Therefore, antide- pressants may have long-term consequence on the architecture, and functioning of the CNS. The function of newly generated neuronal cells in the adult brain remains the source of intense research and debates. Though the hippocampus and neuro- genesis play an important role in depression, these data remain the source of controversies and debates, and the involvement of adult neurogenesis in the etiology of depression to be further charac- terized. Nonetheless, the evidence that stimulation of neurogenesis contributes to the effects of anti- depressants may hold the key for the understanding of the long-term consequences of the effects of antidepressants of the physiopathology of the CNS, and lead to new drugs design, and new strategies to treat depressive disorders. To this aim, deter- mining the cellular and molecular mechanisms of action of antidepressants on neurogenesis will be a determining factor. Acknowledgments P.T. is supported by grants from the NMRC, BMRC, and the Juvenile Diabetes Research Foun- dation. 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