Roles of serotonin in the fetal brain

C H A P T E R

24 Roles of serotonin in the fetal brain Qiuying Zhao, Alexandre Bonnin* Zilkha Neurogenetic Institute and Department of Physiology and Neuroscience, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States *Corresponding author.

I. INTRODUCTION The early appearance of serotonin (5-hydroxytryptamine, 5-HT) during prenatal morphogenesis strongly suggests that 5-HT signaling influences the development and maturation of the fetal brain. 5-HT is an important modulatory factor of neurodevelopmental processes such as cell division, migration, axons projection and pruning, and axonal wiring (Gaspar, Cases, & Maroteaux, 2003). In order to uncover mechanistic links between 5-HT, fetal brain development, and long-term behavioral and neuropathological consequences, it is necessary to know several key aspects such as what are the sources of ligand (5-HT), expression patterns of 5-HT receptors and transporter in the fetal brain during specific developmental periods, and how these parameters may be impacted by adverse exposures in utero. Some of these aspects are described in the following sections.

A. Origins of 5-HT in the fetal brain Serotonergic neurons are generated early in prenatal development, at embryonic day (E) 9.5e10.5 in mice, and during the first month of gestation in primates (Bonnin et al., 2011; Levitt et al., 1982). These neurons are born in very confined areas of the hindbrain, namely the raphe nuclei, which comprise 9 cell groups. The rostral cell group, B6eB9, sends axonal projections into the forebrain whereas the caudal cell group, B1eB5, projects toward the spinal cord (Lidov & Molliver, 1982a; Wallace & Lauder, 1983). Once generated, raphe neurons rapidly synthesize 5-HT and begin to extend abundant axonal projections. These outgrowing serotonergic axons extend toward the forebrain or the

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spinal cord, depending on the raphe nucleus of origin (Muzerelle, Scotto-Lomassese, Bernard, Soiza-Reilly, & Gaspar, 2016). Guidance of these axons within the forebrain appears to depend on classical guidance cues such as Ephrin/Eph receptors, and also possibly involve cues from preexisting tracts (Forero et al., 2017; Teng, Gaillard, Muzerelle, & Gaspar, 2017). For example, ascending serotonergic axons in the mouse run through the medial forebrain buddle, where dopaminergic axons are also observed, and their terminal projections extend as far as the rostral forebrain, including the neocortex as soon as E14/15 (Lidov & Molliver, 1982a). The growth of these axons across the forebrain appears continuous while the development of terminals is a sequential process, happening at specific embryonic periods from one brain region to the next (Lidov & Molliver, 1982a). The serotonergic axonal projection network reaches full maturation after birth in rodents (Lidov & Molliver, 1982b). Given that in early development, several 5-HT receptors are expressed in regions not yet innervated by serotonergic axons (Bonnin, Peng, Hewlett, & Levitt, 2006), the question arose whether raphe neurons are the sole source of fetal brain 5-HT. Pet-1 is a 5-HT neuron-restricted transcription factor whose activity is required to generate most, but not all, 5-HT neurons (Hendricks et al., 2003). Pet-1
/
mice produce only w30% of the normal number of raphe 5-HT neurons (Hendricks et al., 2003). As expected, 5-HT tissue concentration was lower in the hindbrain of Pet-1
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mice compared to wild type mice from E10.5 to E17.5. Yet surprisingly, there was no significant difference in forebrain 5-HT tissue concentration from E10.5 to E15.5 in Pet-1
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mice compared to wild-type mice (Bonnin et al., 2011). This suggested that serotonergic neurons and axons constitute the major source of 5-HT in the hindbrain and

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late fetal forebrain, but not in the early forebrain (before E15.5 in mice). These observations led to investigating alternative exogenous sources of 5-HT reaching the early fetal forebrain. Potential sources include the embryonic peripheral tissue, the maternal blood which would require that maternal 5-HT crosses the placental barrier, or a direct placental source. 5-HT is synthesized from the essential amino acid tryptophan by the rate limiting enzyme tryptophan hydroxylase (TPH). There are two distinct isoforms of TPH in most mammalian species: TPH1 and TPH2. TPH2 is exclusively expressed in neurons (raphe and enteric) (Coˆte´ et al., 2007), whereas TPH1 is expressed in the periphery including the pineal gland, gut enterochromaffin cells, lung neuroepithelial bodies, and thyroid parafollicular cells. This isoform is responsible for the synthesis of blood 5-HT (Dumas, Darmon, Delort, & Mallet, 1989). These TPH isoforms also have different expression timings during development. TPH1 expression was first detected at E14.5 in the pineal gland and at E15.5 in the gut, while TPH2 expression was first detected at E10.5 exclusively in the hindbrain (Coˆte´ et al., 2007; Walther et al., 2003; Zhang, Beaulieu, Sotnikova, Gainetdinov, & Caron, 2004). Based on this timing, a TPH1-dependent, local embryonic peripheral source of 5-HT is unlikely to be reaching the fetal forebrain before E14.5e15.5. A still widely accepted opinion is that maternal blood 5-HT crosses the placenta and is transferred to the fetal circulation (Coˆte´ et al., 2007; Yavarone, Shuey, Sadler, & Lauder, 1993; Yavarone, Shuey, Tamir, Sadler, & Lauder, 1993). Tph1 gene knockout mice only have w3e15% of circulating blood 5-HT compared to normal mice. Although this mouse model provided one way to test if maternal 5-HT reaches the fetal brain, 5-HT tissue concentration was never measured in the forebrain of early embryos from tph1 deficient mothers. Interestingly, however, some embryos from tph1
/
mothers displayed morphological abnormalities during early development (E10.5-E11.5). These results revealed that even though TPH2 can metabolize tryptophan to 5-hydroxytryptophan (5-HTP) in the hindbrain during early development (E10.5-E11.5), maternally derived 5-HT may be important for normal fetal morphogenesis around E10.5-E11.5 (Coˆte´ et al., 2007). However, indirect effects of maternal TPH1 deficiency could not be excluded since tph1
/
mice develop diabetes and cardiac insufficiencies (Coˆte´ et al., 2003; Kim et al., 2010), pathological conditions that can affect fetal development independently of a direct maternal 5-HT effect (Jawerbaum & White, 2010). Furthermore, additional lines of evidence suggested that maternal blood may not be the main source of 5-HT in the fetal brain during early development. For instance, 5-HT transporter (SERT or 5-HTT; slc6a4) knockout (slc6a4
/
) mice have no

detectable blood and platelet 5-HT (Chen et al., 2001), yet the concentration of 5-HT in the forebrain of embryos from slc6a4
/
mothers was normal at E12.5 (Bonnin et al., 2011). This demonstrated directly that maternal blood is not the main source of fetal blood and forebrain 5-HT, at least from E12.5 on. Moreover, in vivo (Robson & Senior, 1964) and ex vivo experiments have directly shown that maternal 5-HT does not efficiently cross the placenta barrier during the fetal period. In particular, ex vivo dual perfusion of live mouse placentas showed that only a small fraction (w0.3%) of physiological concentrations of 5-HT injected through the uterine artery (maternal input) reached the fetal output (umbilical vein) during a 30 min perfusion period (Bonnin et al., 2011). Also, ex vivo perfusions of human term placentas (37e41 gestation weeks) show only negligible maternal to fetal 5-HT transfer; i.e., less than 1% of the physiological concentrations of 5-HT injected into the maternal side of human placental cotyledons (input) reached the fetal output (umbilical vein) during a 120 min perfusion period (Velasquez et al., in preparation). Overall, these studies suggested that exogenous, nonraphe sources are providing 5-HT to the developing forebrain from E10.5 to E15.5. More recently, a placental source of 5-HT to the fetal brain has been identified (Bonnin et al., 2011). Consistent with earlier results demonstrating that injection of tryptophan (but not 5-HT) in pregnant rats increased fetal body and fetal brain 5-HT concentration (Howd, Nelson, & Lytle, 1975), this essential amino acid is metabolized to 5-HTP or/ and 5-HT in the placenta. 5-HT is synthesized from tryptophan by TPH1 and subsequently aromatic amino acid decarboxylase (AADC) enzymes, which are both expressed in the syncytiotrophoblastic cell layer of the mouse placenta from E10.5 to E14.5 (Bonnin et al., 2011). This placental synthetic capacity was not only observed in mice but also in humans at 11 weeks of gestation. In addition, ex vivo perfusions demonstrated that tryptophan injected into the maternal uterine artery is rapidly metabolized to 5-HT, which is released into the fetal blood stream through the umbilical artery (Bonnin et al., 2011). These studies suggested placentally derived 5-HT could directly influence 5-HT-dependent neurogenic processes in the fetal compartment, and therefore play major roles in fetal brain development (Fig. 24.1).

B. Roles of 5-HT in the fetal brain The early appearance of 5-HT neurons in the fetal brain has led to numerous speculations regarding a role for 5-HT in mediating, or modulating, specific aspects of fetal brain development (Aitken & To¨rk, 1988;

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C. 5-HT1 receptors

FIGURE 24.1 Exogenous and endogenous sources of 5-HT in the fetal brain. A direct transfer of 5-HT from the maternal blood to the fetal brain may occur before placentation, but as yet to be demonstrated. Post placentation, 5-HT synthesized in the placenta from maternal blood tryptophan reaches the fetal forebrain from E10.5 to E15.5. Placental 5-HTP may provide another indirect source, after conversion to 5-HT in the fetal hindbrain. Dorsal raphe serotonergic neurons in the hindbrain, that project to the forebrain in later embryonic stages (wE15.5 to birth), progressively become the major source of fetal brain 5-HT. AADC, amino acid decarboxylase; FB, forebrain; HB, hindbrain; TPH1/2, tryptophan hydroxylase 1/2; 5-HTP, 5-hydroxytryptophan.

Buznikov, Lambert, & Lauder, 2001; Lidov & Molliver, 1982b; Buznikov et al., 2001; Yavarone et al., 1993a,b). Decades of research have confirmed that 5-HT signaling participates in the regulation of key aspects of fetal brain development including cell proliferation, migration, differentiation, morphogenesis, and axonal projections (Gaspar et al., 2003; Vitalis, Ansorge, & Dayer, 2013). 5-HT produces ontogenic effects through a variety of receptors, transporters, and enzymes. Seven families of 5-HT receptors have been identified to date. Except for the 5-HT3 receptor, which is ligand-gated ion channel receptor complex, all 5-HT receptors are G-protein coupled and initiate cellular responses by induction of specific second messenger cascades: 5-HT1 and 5-HT5 receptor subtypes interact negatively with the adenylyl cyclase via inhibitory G proteins; 5-HT2 receptor subtypes are coupled to the activation of phospholipase C (PLC); and 5-HT4, 5-HT6, and 5-HT7 receptors activate the adenylyl cyclase via stimulatory G proteins (Dale et al., 2017; Hoyer, Hannon, & Martin, 2002). Demonstrated and potential developmental roles of these receptors are summarized in the following sections.

The 5-HT1 class includes 5-HT1a, 5-HT1b, 5-HT1d, 5-HT1e (in humans), and 5-HT1f (Hoyer et al., 1994) receptors, which couple to Gi/o proteins. A detailed spatial and temporal mapping of 5-HT1 receptor expression in the mouse fetal brain was obtained using mRNA in situ hybridization (Bonnin et al., 2006). This study demonstrated highly selective and dynamic expression patterns of 5-HT1a, 5-HT1b, 5-HT1d, and 5-HT1f in the fetal forebrain from E12.5 to birth. For instance, from E12.5 to birth, 5-HT1a showed moderate expression in the striatum and dorsal thalamus, whereas expression intensity increased developmentally in the hippocampus, and displayed a striking medial high to lateral low gradient in the neocortex (Bonnin et al., 2006). Speculatively, these patterns of expression suggest that 5-HT1a may play a role in hypothalamic pituitary adrenal (HPA) function programming (Andrews, Kostaki, Setiawan, McCabe, & Matthews, 2004) and corticogenesis regulation (Lidow, Trakht, & Howard, 1999). In fact, the 5-HT1a receptor was later demonstrated to play a role in neuronal progenitor proliferation (Cheng et al., 2010) 5ht1b and 5ht1d receptor subtypes showed robust and transient expression in the developing dorsal thalamus from E14.5 to E16.5 (Bonnin et al., 2006), which is a period of active thalamocortical axons (TCAs) pathway formation. In fact, subsequent studies demonstrated that 5-HT signaling modulates the netrin1-mediated guidance of thalamic axons through 5-HT1b/1d-mediated decrease in intracellular cAMP in thalamic neurons during this time period (Bonnin, Torii, Wang, Rakic, & Levitt, 2007). The 5-HT1e receptor is not expressed in rodents and its developmental function, if any, remains unknown (Hoyer et al., 1994). 5-HT1f receptor mRNA was detected within proliferative zones of the thalamus, cortex, and caudal ganglionic eminences (GEs) from E14.5 to birth, suggesting a potential modulatory role in the differentiation and/or migration of neuronal and glial progenitors (Bonnin et al., 2006). Outside of the 5-HT1a, 1b/1d subtypes for which roles in neuronal proliferation and axon guidance have been demonstrated, these data suggest that most 5-HT1 receptor subtypes could function as modulators of early fetal brain development. Although this remains to be fully tested.

D. 5-HT2 receptors The 5-HT2 class comprises the 5-HT2a, 5-HT2b, and 5-HT2c receptors, which couple preferentially to Gq/11 proteins to increase the hydrolysis of inositol phosphates and elevate cytosolic Ca2þ. High expression of 5-HT2 receptors was observed in the cortical plate (marginal zone) of the developing cerebral wall, suggesting a

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role in fetal corticogenesis (Lidow et al., 1999). In the human fetal brain, 5-HT2a receptor expression was detected in the dorsomedial thalamic nucleus as early as 21 weeks of gestation (Wai, Lorke, Kwong, Zhang, & Yew, 2011) and in the caudate nucleus and lentiform nucleus at 31e32 weeks of gestation (Hu, Rudd, & Fang, 2012), suggesting a role in development of the thalamic system. 5-HT2b receptor expression was detected in the neural fold and neural tube of the mouse forebrain at E8-E9. During this period, it is thought that 5-HT2b mediates 5-HT action on embryonic morphogenesis, probably by preventing the differentiation of cranial neural crest cells (Choi, Ward, Messaddeq, Launay, & Maroteaux, 1997). 5-HT2c expression was detected in the E16.5 fetal mouse brain, where it is thought to later mediate appetite-related signals and influence postnatal growth (Martin-Gronert et al., 2016). In the human fetal brain, 5-HT2c receptor expression appeared in the dorsomedial nucleus of the developing thalamus at 21 weeks of gestation and in the ventrolateral and the centromedian nuclei of the thalamus of fetal brain at 31e32 weeks of gestation (Wai et al., 2011). Taken together, these observations suggest that 5-HT2 receptors are part of the 5-HT-dependent molecular pathway modulating fetal brain development.

E. 5-HT3 receptors The 5-HT3 receptors constitute a unique family of ligand-gated ion channel receptors that are modulated by intracellular cyclic AMP (Hoyer et al., 1994). To date, 5-HT3a and 5-HT3b receptors have been identified in rodents and humans (Davies et al., 1999; Hammer et al., 2012; Maricq, Peterson, Brake, Myers, & Julius, 1991), and three additional subunits (5-HT3c, 5-HT3d, and 5-HT3e) have been identified in humans (Niesler et al., 2007). In the CNS, 5-HT3 receptors are first observed at E12 in the subpallial GEdthe major source of interneurons in the basal telencephalon (Johnson & Heinemann, 1995; Tecott, Shtrom, & Julius, 1995). The 5-HT3a receptor is expressed in pioneer CajaleRetzius cells of the marginal zone at E12 and in a subpopulation of late-generated GABAergic neurons arising from the caudal parts of the GE at E14 and E16-17 (Vitalis et al., 2013). This receptor appears required for the migration and proper positioning of reelin-expressing caudal GE-derived interneurons in the neocortex (Murthy et al., 2014). Whether the 5-HT3b is a major determinant of 5-HT function the CNS is still a subject of debate. It has been suggested that 5-HT3a and 5-HT3b receptors expressed in the human fetal brain, especially in the hindbrain and thalamus, may contribute to the predisposition for bipolar affective disorders (Hammer et al., 2012). The expression patterns and functions of 5ht3c-e

receptors in the fetal CNS have yet to be investigated. These studies overall point to a potential developmental interaction between the 5-HT3a/5-HT3b receptors and the risk for mood disorders, suggesting once more an intricate connection between fetal brain development and serotonergic function.

F. 5-HT4 receptors The 5-HT4 receptors couple to the stimulatory Gs protein and include 4 isoforms (5-HT4a, 5-HT4b, 5-HT4e, 5-HT4f) in mouse (Hernandez & Janusonis, 2010) and at least 10 different splice variants (5-HT4a, 5-HT4b, 5-HT4c, 5-HT4d, 5-HT4e, 5-HT4f, 5-HT4g, 5-HT4hb, 5-HT4i, and 5-HT4n) in human (Bockaert, Claeysen, Compan, & Dumuis, 2004). In the mouse fetal brain, 5-HT4 receptors show very low expression at E12-E14. The expression of 5-HT4a and 5-HT4b, but not 5-HT4e and 5-HT4f, receptors gradually increases from E14 to E18, around the time thalamocortical projections reach the telencephalon (Hernandez & Janusonis, 2010; Kamel et al., 2007). In humans, 5-HT4 receptor immunoreactivity only appeared during late gestation, at 32 weeks, in fibers located in the vicinity of the thalamus dorsomedial nucleus; the spatial association with the development of serotonergic projections in this area suggested that 5-HT4 signaling may contribute to the pathophysiology of neuropsychiatric disorders (Wai et al., 2011), although this remains to be demonstrated.

G. 5-HT5 receptors The 5-HT5 receptor family consists of two members: 5-HT5a and 5-HT5b receptors. The 5-HT5a receptor has been identified in rodents and humans, whereas the 5-HT5b receptor is expressed only in rodents (Nelson, 2004). In the adult brain, 5-HT5a receptors appear to primarily couple to Gi/o proteins to inhibit adenylyl cyclase activity. 5-HT5b receptors coupling has not been characterized (Hoyer et al., 2002; Nelson, 2004). The roles and signal transduction pathways triggered by 5-HT5a and 5-HT5b receptors in the fetal brain have yet to be identified.

H. 5-HT6 receptors The 5-HT6 receptor which is coupled to the stimulatory Gs protein and activates cAMP production, is expressed in rodents and humans. The 5-HT6 receptor messenger RNA is detected in the developing rodent brain as early as E12 and is stably expressed until early postnatal stages (Grimaldi et al., 1998). More detailed analyses revealed that 5-HT6 receptors are expressed in the subventricular zone, intermediate zone, and

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FIGURE 24.2

5-HT receptors mediate trophic functions in the fetal brain. Seven types of 5-HT receptors are divided into four subfamilies according to their pharmacology and intracellular transduction pathways. 5-HT1 receptors preferentially couple to Gi/o proteins and regulate thalamocortical axon (TCA) projections and pruning, proliferation, and migration of neuronal and glial progenitors. 5-HT5 receptors are also coupled to Gi/o proteins, but their role has yet to be investigated. 5-HT2 receptors couple to Gq/11 proteins and participate in the development of thalamic and serotonergic systems, neuronal progenitor proliferation, and differentiation in the neocortex. 5-HT3 receptors are ligand-gated ion channels and contribute to cortical development, dendritic, and axonal formation. Gs protein-coupled 5-HT4, 5-HT6, and 5-HT7 receptors influence thalamocortical projections formation, corticogenesis, and neocortical circuit formation.

cortical plate of the mouse neocortex at E14.5. Furthermore, elegant studies have demonstrated that activation of 5-HT6 receptors decreases neocortical pyramidal neuron migration (Riccio et al., 2011). The effect on the positioning and migration of pyramidal neurons progenitors is mediated through ligand-independent Cdk5 activity during corticogenesis (Jacobshagen, Niquille, Chaumont-Dubel, Marin, & Dayer, 2014). Thus, 5-HT6 receptors have recently been characterized as key modulators of cortical formation in the fetal brain.

I. 5-HT7 receptors The 5-HT7 receptor is Gs-coupled and stimulates adenylate cyclase activity, resulting in an increase in intracellular cAMP (Leopoldo, Lacivita, Berardi, Perrone, & Hedlund, 2011). Other studies also showed an interaction of 5-HT7 receptors with Ga12 proteins (Kvachnina et al., 2005). Dynamic 5-HT7 receptor mRNA expression was observed in human fetal brain in the CA2/3 and CA4 hippocampal subfields and in the thalamus during the second half of pregnancy. The dentate gyrus and cingulate cortex expressed only low and constant levels of 5-HT7 mRNA throughout gestation (Andrews et al., 2004). These results suggested that 5-HT7 receptors may facilitate a neurotrophic role of 5-HT during midembryonic life. Other studies have

shown 5-HT7 receptor expression in E15 mouse striatum and cortex, and E18 hippocampus neuronal cultures, and demonstrated a role in neurite outgrowth and dendritic spines formation (Speranza et al., 2015). Overall, there is good evidence that 5-HT1, 5-HT2, 5-HT3, 5-HT6, and 5-HT7 receptor families in particular contribute to 5-HT function in fetal brain development. Recent studies have provided great progress in our understanding of specific developmental processes mediated by some specific receptor subtypes (e.g., 5-HT1b/ 1d, 5-HT3a, 5-HT6). Nevertheless, for most other receptors only limited descriptive expression data are available. Therefore, a more complete expression map of all 5-HT receptors, and the determination of specific cellular processes they affect, is still needed to better define how 5-HT signaling shapes brain networks formation during development (Fig. 24.2).

II. INFLUENCE OF EPIGENETIC AND ENVIRONMENTAL FACTORS ON 5-HT SIGNALING DURING FETAL DEVELOPMENT As described above, fetal brain 5-HT has multiple origins throughout gestation. Furthermore, several types of fetal cells and neurons transiently synthesize, store, or

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release 5-HT. 5-HT signaling is dependent upon numerous receptors, transporters, and enzymes, all of which show dynamic expression patterns during development. All these parameters likely contribute to the multifaceted regulation of 5-HT effects on fetal brain circuits formation. Over the years, these observations have raised the possibility that derailing 5-HT regulation during development could increase the risks of psychiatric diseases later in life (Bonnin et al., 2011; Bonnin & Levitt, 2012; Brummelte, Mc Glanaghy, Bonnin, & Oberlander, 2017; Gaspar et al., 2003; Velasquez, Goeden, & Bonnin, 2013). Therefore, it is critical to confirm if and how 5-HT signaling during development is altered by epigenetic and environmental perturbations known to increase such risks.

A. Epigenetic influences Epigenetic programming is generally defined as chemical modifications, such as DNA methylation and histone modifications, that influence gene expression and regulate gene function, without changing the DNA nucleotide sequence (Dulac, 2010). These epigenetic modifications have been shown to be important for normal embryonic development and tissue-specific cellular differentiation (Orkin & Hochedlinger, 2011; Ptak & Petronis, 2008), and might constitute a new target for psychiatric interventions (Maze et al., 2014). DNA methylation of cytosine phosphate guanosine (CpG) islands, proximal to transcription promoter sites, induces stable and long-term variations in gene expression (Antequera, 2003). Hence, the durable effects of epigenetic modifications are cumulatively recognized as crucial factors in the relationship between early life experiences and risk of psychopathology later in life. Changes in DNA methylation patterns in the slc6a4 (SERT) gene have been associated with early life adversity and psychiatric disorders. For instance, exposure to maternal depressed mood in the second trimester of pregnancy was correlated with lower maternal and infant slc6a4 promoter methylation (Devlin, Brain, Austin, Oberlander, & Feil, 2010). Exposure to lower maternal care in early postnatal life increased slc6a4 methylation, and also increased anxiety behaviors in infant rhesus macaques (Kinnally et al., 2010). Childhood adversities such as sexual abuse were also associated with increased slc6a4 promoter methylation for long-lasting periods (Beach, Brody, Todorov, Gunter, & Philibert, 2010, 2011). These studies demonstrate a connection between slc6a4 methylation and altered behaviors that are largely influenced by central 5-HT signaling. Nevertheless, more epigenetic studies are needed to confirm the feasibility of using early slc6a4 methylation patterns as

biomarkers of later psychiatric disorders vulnerability (Booij, Wang, Le´vesque, Tremblay, & Szyf, 2013). Besides the 5-HT transporter, several studies have investigated whether adverse events also affect epigenetic regulation of 5-HT receptors expression. For instance, it was shown that maternal adverse experience during pregnancy significantly increased placental 5-HT2a receptor gene methylation, and was associated with infant neurobehavioral deficits (Paquette et al., 2013). Interestingly, 5-HT2a receptor activation could in turn regulate histone deacetylases 2 (HDAC2) gene promoter activity, and thus trigger histone modifications affecting the expression of other genes, as observed in mice and in human frontal cortex of schizophrenic patients (Kurita et al., 2012). Thus, altered 5-HT2a receptor function is thought to be involved in schizophreniarelated disorders. This emphasizes the necessity to further study the developmental and long-term consequences, and molecular mechanisms driving 5-HT2a receptor gene epigenetic modifications triggered by prenatal adversity (Rasmussen et al., 2010). Speculatively, epigenetic modifications of other 5-HT receptor genes could also play important roles in the fetal programming of mental disorders. For instance, perinatal maternal stress in rats was shown to decrease 5-HT1alike immunoreactivity in the hippocampus of the adult offspring (Van den Hove et al., 2006). An increased DNA methylation of the htr1a gene promoter region was observed in schizophrenia and bipolar disorder (Carrard, Salzmann, Malafosse, & Karege, 2011). These observations are not correlated, but they suggest that adverse prenatal events such as maternal stress could have long-lasting effects on 5-HT1a receptor function in the offspring brain via epigenetic modification of htr1a gene promoter activity in utero. This highlights the need for further studies testing directly whether in utero maternal experience can epigenetically change key components of 5-HT signaling.

B. Environmental influences Early life exposure to adversity put some children at risk of neuropsychiatric diseases (Khandaker & Dantzer, 2016; Khandaker, Zimbron, Lewis, & Jones, 2013; Golam M). A relevant line of research in animal models has been focused on the relationship between perinatal environment, at prenatal and postnatal time, and alterations of 5-HT signaling in the offspring brain (Boyce & Ellis, 2005; Brown et al., 2004). One of the earliest examples is provided by a study showing that maternal psychological stress during late pregnancy increases maternal plasma and fetal brain tryptophan concentration, subsequently increasing 5-HT concentration in the fetal brain (Peters, 1990). In more recent studies, chronic

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unpredictable stress in pregnant rats led to higher level of 5-HT and lower level of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and decreased 5-HT1a receptor and SERT expression in E20 fetuses (Huang et al., 2012). These studies suggested that maternal stress-induced alteration of 5-HT content in the fetal brain may affect development during the perinatal period. A related, and clinically relevant, environmental influence on prenatal 5-HT function may result from the therapeutic treatment of maternal depression with selective 5-HT reuptake inhibitors (SSRIs). Indeed, depression has a relatively high prevalence during pregnancy (Stewart, 2011) and pharmacologic intervention with SSRI antidepressants is commonly prescribed (Cooper, Willy, Pont, & Ray, 2007). But treating maternal depression during pregnancy presents a therapeutic dilemma, as epidemiological studies have suggested an association between in utero SSRI exposures and increased risks of adverse perinatal outcomes, including autism spectrum disorder (ASD), attention-deficit/ hyperactivity disorder (ADHD), depression and anxiety disorders, and other sequelae that span broad developmental domains during the lifetime (Brown et al., 2016; Brown, Hussain-Shamsy, Lunsky, Dennis, & Vigod, 2017; Brown et al., 2017a, b; Hadjikhani, 2010; Harrington, Lee, Crum, Zimmerman, & Hertz-Picciotto, 2014; Kaplan, Keskin-Arslan, Acar, & Sozmen, 2016; Man et al., 2017; Rai et al., 2013; Sujan et al., 2017; Velasquez et al., 2013). However, forgoing treatment to avoid fetal risks exposes both mother and fetus to the effects of untreated depression and stress which, as discussed above, are associated with adverse outcomes that also include ADHD, developmental delays, and psychiatric disorders later in life (Diego et al., 2004; Fox, Levitt, & Nelson, 2010; Oberlander, Warburton, Misri, Aghajanian, & Hertzman, 2006; Oberlander & Vigod, 2016; Velasquez et al., 2013). It should be noted, however, that the association between ASD and prenatal exposures to SSRIs is not entirely demonstrated. Studies have reported increased risks following SSRI exposure during pregnancy (Croen, Grether, Yoshida, Odouli, & Hendrick, 2011; Gidaya et al., 2014; Harrington et al., 2014; Rai et al., 2013), or untreated gestational depression but not SSRI exposure (Ronald, Happe´, Dworzynski, Bolton, & Plomin, 2010), or found no increased risks following maternal SSRI treatment (Brown et al., 2017a,b; Clements et al., 2015; Hviid, Melbye, & Pasternak, 2013; Sorensen et al., 2013; Sujan et al., 2017). Therefore, it is not entirely clear whether SSRIs aggravate or ameliorate the impact of maternal depression and stress on the developing fetal brain. SSRIs indirectly target 5-HT signaling through inhibition of the plasma membrane 5-HT transporter SERT (Blakely & Edwards, 2012; Qian et al., 1997). Furthermore, most SSRIs are readily transferred from mother to fetus through the placenta

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(Velasquez et al., 2013, 2016). As described in the previous sections, 5-HT plays important trophic roles in the fetal brain, therefore it is usually assumed that exposure to SSRIs during pregnancy could affect 5-HT-dependent neurogenic processes in the developing fetal brain (Brummelte et al., 2017; St-Pierre, Laurent, King, & Vaillancourt, 2016). This possibility is supported by animal model studies showing that pre and postnatal SSRI exposures reduce adult serotonergic innervation and function and elicit depressive- and anxiety-like behaviors in adulthood (Altieri et al., 2015; Ansorge, Morelli, & Gingrich, 2008; Bairy, Madhyastha, Ashok, Bairy, & Malini, 2007; Shanahan et al., 2009). Although little is known about the acute effects of SSRIs in utero on fetal brain development, particularly in the context of underlying maternal stress or depression, some animal studies suggest that these drugs could indeed impact 5-HT-dependent neurogenic processes. For instance, the SSRI citalopram (CIT) was shown to decrease Tph2 and Slc6a4 gene expression in the midbrain after neonatal exposure, resulting in long-term behavioral abnormalities (Maciag et al., 2006). A more recent study showed that in utero exposure to CIT reduced neurogenesis in various proliferative zones of the mouse fetal brain at E17 (King, Velasquez, Torii, & Bonnin, 2017). Nevertheless, it is important to mention that SSRI-induced changes in early serotonergic signaling do not necessarily lead to negative outcomes for the offspring, particularly in the context of maternal stress effects (Brummelte, Galea, Devlin, & Oberlander, 2013; Rayen, Gemmel, Pauley, Steinbusch, & Pawluski, 2015). At the time of this writing, the consequences of in utero exposure to SSRIs in relation to maternal depression effects are still largely unclear. This emphasizes the necessity of further studying the fetal effects of SSRI exposures, especially in the context of maternal stress and genetic and epigenetic variations in animal models, in order to better inform future therapeutic directions. A different type of environmental stressor, maternal inflammation, was recently shown to also alter fetal brain 5-HT metabolism and function. Maternal inflammation triggered by intrauterine endotoxin or polyinosinic:polycytidylic acid (PolyI:C) exposure increased L-tryptophan concentration and 5-HT synthesis in the placenta and fetal brain, leading to 5-HT-mediated alteration of serotonergic axon outgrowth and excitotoxic injury of TCA in the fetal brain (Goeden et al., 2016; Williams et al., 2017). These perturbations of 5-HT system function and development during sensitive periods of pregnancy may be contributing to previously described inflammation-related long-term effects on offspring brain function (Bauman et al., 2014; Hsiao, McBride, Chow, Mazmanian, & Patterson, 2012). In summary, many studies to date have uncovered specific effects of various environmental exposures on

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5-HT-dependent neurogenic processes in the fetal brain. Understanding, mechanistically, how these exposures alter 5-HT-dependent neurogenic processes during fetal neurodevelopment, and how such alterations lead to psychiatric disorders later in life remain important future directions.

III. CONCLUSION Although 5-HT has been known as a neuromodulator of adult brain function for over five decades, its role in the fetal programming of mental disorders is only beginning to be realized. 5-HT is the earliest neurotransmitter to appear in the fetal brain, originating from multiple sources from the early placenta to later endogenous serotonergic neurons and axons. 5-HT signaling regulates neurogenesis, neuronal differentiation and migration, and axonal circuit formation throughout the fetal brain, via many different receptors. Although great progress has been made over the last few decades, the neurodevelopmental role of only a handful of these receptors has been characterized. The 5-HT transporter is also an important, albeit indirect, player in 5-HT signaling modulatory role of fetal brain development. In addition, it appears that gene expression levels of some of these key components of 5-HT signaling can be epigenetically altered in utero by maternal experiences, leading to long-term changes in serotonergic function. Moreover, environmental factors ranging from stress to therapeutic drugs exposure and inflammation can, more directly, biochemically alter 5-HT metabolism and signaling in the fetal brain. Therefore, clear mechanistic understanding of how these exposures alter 5-HT-dependent neurogenic processes during fetal neurodevelopment, and how such alterations lead to abnormal brain function later in life, is steadily emerging. Exciting new aspects of 5-HT role in the fetal programming of mental disorders will undoubtedly be uncovered in the coming years.

Acknowledgments This work was supported by NIMH (5R01MH106806) and NARSAD (Brain & Behavior Research Foundation) to A.B.

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IV. SEROTONIN AND BEHAVIOURAL CONTROL