Serotonergic Regulation of Adult Neurogenesis

Among monoamines, the 5-HT control of adult neurogenesis has been the most largely investigated, notably when studying the consequences of serotonergic antidepressants. Indeed, chronic increases in extracellular level of 5-HT by selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, or paroxetine have repeatedly been shown to increase hippocampal neurogenesis in basal conditions and reverse the suppressive effects of stress or treatments associated with stressful events (Malberg et al. 2000; Lee et al. 2001; Malberg and Duman 2003; Encinas et al. 2006; Chen et al. 2006; Jayatissa et al. 2006; Qiu et al. 2007; Marcussen et al. 2008; Wang et al. 2008). Recent studies also indicated that fluoxetine-induced increases in neurogenesis can depend on age (Cowen et al. 2008; Couillard-Despres et al. 2009), on genetic background (Miller et al. 2008), and on interactions with the hypothalamic-pituitary-adrenal axis activity (Huang and Herbert 2006).

Consistent with a stimulatory role of 5-HT, we provided the first evidence that long-lasting 5-HT depletion induced by neurotoxic lesion of 5-HT-containing cells in the raphe nuclei produced significant decreases in cell proliferation and neurogenesis (Brezun and Daszuta 1999). This effect was reversed by grafting embryonic raphe tissue, containing 5-HT neurons, in the hippocampus (Brezun and Daszuta 2000a), suggesting a local 5-HT control. Other kinds of 5-HT depletion may reproduce these effect (Ueda et al. 2005; Rosenbrock et al. 2005; Zhang et al. 2006), or not (Huang and Herbert 2005; Jha et al. 2008). Reasons might be in genetic and gender differences, as well as the kind of neurotoxic lesion (intra cerebro ventricular (ICV) vs intra-raphe injections of 5,7-DHT) and duration of 5-HT depletion. Indeed, injured 5-HT neurons have remarkable capacities for regrowth (Azmitia et al. 1978), as shown by the progressive reinnervation of the hippocampus observed after a partial lesion, which was also associated to a recovery of cell proliferation (Brezun and Daszuta 2000b). Although the mechanism of action of neurotransmitters and the receptor subtypes that are expressed by neural precursors and surrounding cells in neurogenic niches remain to be precisely determined, several 5-HT receptor subtypes, such as 5-HT1A and 5-HT1B, 5-HT2A, and 5-HT2C, and 5-HT4, are involved in the regulation of adult neurogenesis (Jha et al. 2008C; Banasr et a4l. 2004; Lucas et al. 2007).

9.3.2.1 Implication of 5-HT1A and 5-HT1B Receptors

A number of studies have also demonstrated the positive implication of 5-HT1A receptors in the regulation of hippocampal neurogenesis (Huang and Herbert 2005; Banasr et al. 2004; Radley and Jacobs 2002; Santarelli et al. 2003). Further, both acute and chronic activation of 5-HT1A receptors by 8-OHDPAT administration increase cell proliferation in the SVZ and, later, on neurogenesis in the OB (Banasr et al. 2004). As observed with fluoxetine, this mediation depends on the genetic background (Holick et al. 2008) and complex interactions with corticosterone level (Huang and Herbert 2006). Postsynaptic 5-HT1A receptors, not somatic 5-HT1A autoreceptors that desensitize over time, are involved in this effect in the SGZ (Huang and Herbert 2005; Banasr et al. 2004). Indeed, the increase in cell proliferation induced by chronic administration of 8-OHDPAT persists in 5-HT depleted rats, indicating that this stimulatory effect is not dependent on the integrity of 5-HT transmission. Interestingly, findings that are more recent suggest that chronic activation of 5-HT1A receptors has also a positive effect on the survival of hippocampal granule cells (Soumier et al. 2010). This result is consistent with the expression of 5-HT1A receptors by mature granule cells (Pompeiano et al. 1992; Kia et al. 1996) and is further supported by the neuroprotective action observed after stimulation of 5-HT1A receptors in various models of brain damage (Schaper et al. 2000; Mauler and Horvath 2005; Bezard et al. 2006).

As for 5-HT1A, the 5-HT1B agonist sumatriptan stimulates cell proliferation in the SGZ through activation of 5-HT1B heteroreceptors (Banasr et al. 2004). However, in the SVZ, the decrease and increase in cell proliferation observed after administration of 5-HT1B agonist and antagonist (GR 127935), respectively, are more likely due to the decrease and increase in 5-HT transmission modulated by 5-HT1B terminal autoreceptors, since sumatriptan does not affect cell proliferation in 5-HT depleted rats (Banasr et al. 2004). These data suggest that multiple receptor subtypes may be involved in the 5-HT control of neurogenesis in forebrain regions.

9.3.2.2 Implication of 5-HT2C Receptors

Forebrain Regions

In the SVZ, cell proliferation is enhanced by administration of the 5-HT2A/2C agonist DOI, and this effect is reproduced by the selective 5-HT2C agonist, RO 600175 (Banasr et al. 2004). The lack of effect of the 5-HT2C antagonist SB206553 is consistent with a phasic 5-HT stimulation of cell proliferation in this region. Further, increases in neurogenesis in the OB following either acute or chronic administration of RO600175 indicate that the 5-HT2C receptors involved in this modulation do not desensitize over time (Banasr et al. 2004). By contrast, this treatment does not affect the survival of new neurons in the OB (Soumier et al. 2010), supporting the view that differential mechanisms are involved in the regulation of proliferation and survival of newly formed cells. Since choroid plexus expresses one of the highest concentrations of 5-HT2C receptors in the brain (Palacios et al. 1990), secretion of trophic factors by this structure (Chodobski and Szmydynger-Chodobska 2001), such as VEGF, may indirectly contribute to the effects of 5-HT2C agonists on cell proliferation in the SVZ.

More surprisingly, RO 600175 treatment also produces an increase in gliogenesis in the striatum and prefrontal cortex (Soumier et al. 2010). These two regions have been considered as showing clear adult neurogenic activity in response to brain injury (Magavi et al. 2000; Kokaia and Lindvall 2003). However, a low neurogenic activity is also present in basal conditions, which has been attributed to progenitors derived from the SVZ and/or local parenchymal progenitors (Cameron and Dayer 2008; Luzzati et al. 2006). We showed that in both regions, RO 600175 increases the total number of newly formed cells mainly expressing a glial marker (NG2, a marker of oligodendrocyte progenitors). This treatment did not induce a neuronal phenotype or affect the survival of these new cells. The regional analysis in the upper versus deeper cortical layers and medial versus lateral striatal subregions showed similar increases in every region. No gradient in the number of new cells could be detected, suggesting that these changes probably target local progenitors and do not involve a migration of progenitors from the SVZ. However, the lack of overlap with the distribution of the 5-HT2C receptors in these regions also favors the hypothesis that these effects are indirect.

Hippocampus

In the DG, acute or chronic activation of 5-HT2A/2C receptors does not affect cell proliferation or neurogenesis, as also observed with the selective 5-HT2C agonist (Banasr et al. 2004; Jha et al. 2006). By contrast, chronic blockade of 5-HT2A/2C (Jha et al. 2006; Soumier et al. 2009) or 5-HT2C receptors (Soumier et al. 2010), but not acute (Banasr et al. 2004), stimulates this process. These results underpin the need for long-term inactivation of 5-HT2C receptors. Consistent with the constitutive activity of this receptor subtype (Berg et al. 2005), only the selective 5-HT2C receptor inverse agonist (SB 243,213) induced an increase in cell proliferation, while the neutral antagonist (SB 242,084) had no effect. Notably, it has been demonstrated that 5-HT2C receptor inverse agonists are more efficacious in enhancing DA release (De Deurwaerdere and Spampinato 2001), probably via GABA-ergic inhibitory interneurons (Invernizzi et al. 2007). As previously mentioned, GABA has a negative influence on cell proliferation and GABA-ergic interneurons are known to express 5-HT2C receptors in various brain regions (Invernizzi et al. 2007; Serrats et al. 2005; Liu et al. 2007). Thus, besides the "more direct" 5-HT2C-mediated GABA-ergic influence on precursor cells (Ge et al. 2007), a 5-HT2C-mediated activation of NA (Millan et al. 2000) or DA projections can modulate hippocampal neurogenesis (Hoglinger et al. 2004; Kulkarni et al. 2002).

Regarding cell survival, none of the selective 5-HT2C agonist or antagonists affected this phase of neurogenesis in every brain region examined (Soumier et al. 2010). Administration of 5-HT2A/2C agonist has been shown to modulate hippocampal and cortical levels of BDNF (Vaidya et al. 1997), a trophic factor known to promote particularly cell differentiation and survival (Sairanen et al. 2007). However, this effect on BDNF levels involves 5-HT2A and not 5-HT2C receptors. In line with this result, we did not detect changes in hippocampal BDNF levels following administration of SB 242,084 or SB 243,213. Altogether, these data reinforce the lack of implication of 5-HT2C in cell survival.

9.3.2.3 5-HT2C Receptors, Adult Neurogenesis, and Depression-Anxiety Disorders

Both hippocampal neurogenesis and trophic factor levels show opposite changes in stressful situations and following antidepressant treatments. These observations led, a few years ago, to "the neurogenic/neurotrophic theory of depression and antidepressant action" (Duman and Monteggia 2006), based on the hypothesis that changes in neuroplasticity may compromise or favor neuronal function (Duman et al. 1997; Jacobs et al. 2000). A large number of studies and reviews have contributed to the debate (Sahay and Hen 2007; Paizanis et al. 2007; Pittenger and Duman 2008; Czeh and Lucassen 2007; Feldmann et al. 2007; Vollmayr et al. 2007; Fuchs 2007). Most of them agree with the fact that reducing neurogenesis by using different methods does not result in depressive-like behaviors, while induction of neurogenesis is required for the behavioral action of antidepressants (Santarelli et al. 2003; Vollmayr et al. 2003; Airan et al. 2007).

Interestingly, 5-HT2C receptors are thought to play a complex role in the regulation of mood, since both 5-HT2C agonists and antagonists have antidepressant-like effects (Millan 2005; Rosenzweig-Lipson et al. 2007). Likewise, both 5-HT2C agonist and antagonist increase neurogenesis, although in a region-dependent manner: Activation of 5-HT2C receptors leads to a stimulation of cell proliferation in the SVZ, while the blockade has the same effect in the SGZ. One possible explanation is that this 5-HT2C region-dependent regulation may be related to mRNA editing of this receptor subtype. Indeed, the constitutive activity at 5-HT2C sites is modulated by mRNA editing that generates unique isoforms of proteins in a cell- and/or tissue-specific manner, the unedited isoform displaying the greatest basal activity (Niswender et al. 1999). Thus, it would be of interest to compare 5-HT2C mRNA editing in different limbic structures, including hippocampus, following various stressful events and antidepressant treatments. In line with this, it has to be noted that increased 5-HT2C mRNA editing in cortical regions has been associated with depression and suicide (Gurevich et al. 2002).

Interestingly, we also demonstrated that 5-HT2C agonist increases cortical glio-genesis. Growing evidence indicates that glial elements are involved in the pathophysiology of depression (Rajkowska and Miguel-Hidalgo 2007) and that cortical gliogenesis is modulated by stress and antidepressants (Banasr and Duman 2007). Thus, the question of a possible functional implication of increased gliogenesis by activation of 5-HT2C receptors constitutes a promising target of investigation.

Finally, regarding the brain circuits involved in depression and anxiety, we observed a selective implication of the ventral hippocampus (VH) in cell proliferation following blockade of 5-HT2C receptors. These data may be related to anatomical and functional differences reported when comparing the ventral (temporal pole) and the dorsal (septal pole) hippocampus (Moser and Moser 1998; Bannerman et al. 2004). The projections of the VH to the prefrontal cortex and its strong connection with the amygdala support the view that this subregion is particularly involved in "emotional circuitry" and is more specialized for the control of anxiety and depression-related functions, whereas the DH is more implicated in cognitive functions (Bannerman et al. 2004; Engin and Treit 2007). This regional dissociation regarding the implication of new neurons in cognitive processes may not be so rigorous (Snyder et al. 2008). However, recent studies demonstrated selective decreases in neurogenesis in the VH following various stress exposures that elicit depressive-like behavior in the adult (Jayatissa et al. 2006; Kim et al. 2005; Lagace et al. 2006). Prenatal stress exposure also induced a reduction in neurogenesis in the VH selectively, which is associated with anxious behavior (Zuena et al. 2008). Conversely, the selective increase in cell proliferation in the VH following 5-HT2C antagonist administration is consistent with the preferential implication of these receptors in emotional response. In contrast to their sparse expression in DH, 5-HT2C receptors are, to a major extent, expressed in VH (Holmes et al. 1995), and their activation by injecting 5-HT2C agonists in this subregion produced anxiogenic effects (Alves et al. 2004). In line with these data, agomelatine, a new antidepres-sant with anxiolytic property, acting partly as a 5-HT2C antagonist, also increases, selectively, cell proliferation and neurogenesis in this subregion (Banasr et al. 2006). Altogether, these results suggest that the control of adult neurogenesis in the VH may be related to anxiolytic-antidepressant effects.

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