Serotonin and Brain Development

SEROTONIN AND BRAIN DEVELOPMENT

Monsheel S. K. Sodhi and Elaine Sanders-Bush Departments of Pharmacology and Psychiatry Vanderbilt University Nashville, Tennessee 37232

I. Introduction II. The Discovery of Serotonin and Classification of Serotonin Receptors A. Distribution and Projections of the Serotonergic System III. The Role of Serotonin in Developmental Plasticity A. Serotonergic Projections during Brain Development B. Growth Factors Influencing the Development of Serotonergic Neurons C. The Role of Serotonin as a Growth Factor D. Serotonin Receptors and Developmental Plasticity IV. Manipulation of the Serotonergic System Alters Synaptic Plasticity A. Tryptophan and Serotonin Depletion Studies B. Experimental Models of Synaptic Plasticity V. Does Dysfunction of Serotonergic Signaling Result in Impaired Brain Development? A. The Role of Serotonin in Learning and Memory B. Autism and Serotonin C. The Role of Serotonin in Stress and Anxiety D. Serotonergic Influences on Synaptic Plasticity in AVective Disorders E. Altered Synaptic Plasticity in Schizophrenia F. Down’s Syndrome, Mental Retardation, and Serotonin VI. Conclusions References

The role of the serotonergic system in the neuroplastic events that create, repair, and degenerate the brain has been explored. Synaptic plasticity occurs throughout life and is critical during brain development. Evidence from biochemical, pharmacological, and clinical studies demonstrates the huge importance of an intact serotonergic system for normal central nervous system (CNS) function. Serotonin acts as a growth factor during embryogenesis, and serotonin receptor activity forms a crucial part of the cascade of events leading to changes in brain structure. The serotonergic system interacts with brain-derived neurotrophic factor (BDNF), S100 , and other chemical messengers, in addition to its cross talk with the GABAergic, glutamatergic, and dopaminergic neurotransmitter systems. Disruption of these processes may contribute to CNS disorders that have been associated with impaired development. Furthermore, many psychiatric drugs alter serotonergic activity and have been shown to create changes in brain structure with long-term treatment. However, the mechanisms for their

INTERNATIONAL REVIEW OF 111 Copyright 2004, Elsevier Inc. NEUROBIOLOGY, VOL. 59 All rights reserved. 0074-7742/04 $35.00 112 SODHI AND SANDERS-BUSH therapeutic eYcacy are still unclear. Treatments for psychiatric illness are usually chronic and alleviate psychiatric symptoms, rather than cure these diseases. Therefore, greater exploration of the serotonin system during brain development and growth could lead to real progress in the discovery of treatments for mental disorders.

I. Introduction

Serotonin (5-hydroxytryptamine, 5-HT), the ‘‘happy hormone,’’ has a phylo- genetically ancient role in neural transmission (Turlejski, 1996). Because the serotonergic system has a widespread distribution in the CNS, it influences almost every sphere of mammalian physiology, from cardiovascular regulation (Miyata et al., 2000; Nebigil et al., 2000; Thorin et al., 1990), respiration, the gastrointestinal system (Kato et al., 1999), pain sensitivity, and thermoregulation to more centrally controlled functions. The latter include the maintenance of circadian rhythm, appetite, aggression, sensorimotor activity, sexual behavior, mood, cognition, learning, and memory. Hence drugs with serotonergic activity are used to treat the aVective disorders schizophrenia (AbiDargham et al., 1996; Breier, 1995; Kapur and Remington, 1996; Meltzer, 2002; Ohuoha et al., 1993; Sodhi and Murray, 1997), anxiety (Gross et al., 2002), stress, eating disorders (Bray, 2000; GuyGrand, 1995; Halford, 2001; Heal et al., 1998; Heisler et al., 1998b; Hesselink and Sambunaris, 1995; Jallon and Picard, 2001; Koponen et al., 2002; Luque and Rey, 1999; McNeely and Goa, 1998; Prasad, 1998; Weissman, 2001), and deliberate self-harm (Holden, 1995). In addition, personality dysfunctions such as addictive behaviors, aggression, psychopathic and sociopathic behavior, attention-deficit hyperactivity, and autism are also associated with altered serotonergic transmission. Indeed, new serotonin receptor ligands are being explored as possible treatments for Alzheimer’s disease, as they appear to improve memory (Sumiyoshi et al., 2001), obesity (Bray, 2000; Rothman and Baumann, 2002; Stunkard and Allison, 2003; Wechsler, 1998), and epilepsy (Chadwick et al., 1977; Chugani and Chugani, 2003; Dailey et al., 1992; Deahl and Trimble, 1991; Fromm et al., 1977; Heisler et al., 1998b; Lunardi et al., 1995; Monaco et al., 1995; Savic et al., 2001; Statnick et al., 1996; Yan et al., 1994). Although increasing knowledge of serotonergic function is propelling many advances in the therapeutics of psychiatric and behavioral disorders, drugs in clinical use often treat the disease symptoms instead of relieving or preventing the causes. Moreover, treatment regimes are often lengthy or lifelong, sometimes with severe side eVects. As yet the causes of psychiatric disease are unknown, therefore the role of serotonin in the etiology or progression of these disorders SEROTONIN AND BRAIN DEVELOPMENT 113 requires exploration in order to facilitate improvements in medication and prog- noses. There is increasing support for the hypothesis that impaired development and synaptic plasticity contribute to the etiologies of many central nervous system (CNS) diseases. Plasticity is defined as functionally relevant structural adaptations performed by the CNS following genetic or environmental challenges. Neuronal plasticity is essential for the survival of an individual in a constantly changing environment. It is a dynamic process based on the ability of neuronal systems, brain nuclei synapses, single nerve cells, and receptors to adapt to challenges. Plasticity reveals itself in a number of ways, which range from altered gene expression or changes in neurotransmitter release to changes in behavior or phenotype. Synaptic plasticity is constant throughout life and is especially important during development. Connections between neurons of the CNS are capable of being dismantled and reconstructed in response to changes in the physiological environment, therefore stress, malnutrition, sleep, hormones, and drugs can all produce changes in brain structure. Accumulating research suggests that serotonin plays an important role in synaptic plasticity and brain development. In this review we attempt to explore this evidence and its implications for impaired brain development and psychiatric illness.

II. The Discovery of Serotonin and Classification of Serotonin Receptors

The chemical 5-hydroxytryptamine (5-HT) was first isolated in serum and, because of its powerful vasoconstrictive eVects, was dubbed ‘‘serotonin’’ (Rapport, 1948). Serotonin was later detected in the brain (Twarog and Page, 1953). In 1957, Gaddum and Picarelli reported the existence of multiple serotonin receptor subtypes, which they called 5-HT-M and 5-HT-D, after their antagonists, morphine and dibenzyline, respectively. Peroutka and Snyder (1979) reclassified these receptors based on radioligand-binding studies in brain hom- 3 ogenates. The 5-HT1 receptor was labeled by [ H]5-HT, whereas the 5-HT2 receptor (corresponding to 5-HT-D) was sensitive to the dopamine receptor 3 ligand [ H]spiperone. By 1986, the M receptors were renamed 5-HT3 receptors (Bradley,1986),werefoundtobetheonlyionotropicsubtypeofthe5-HTreceptor, and were detected to be at low density in limbic and striatal areas (Abi-Dargham et al., 1993). [3H]Lysergic acid diethylamide (LSD), a psychotomimetic com- pound with a structure similar to serotonin, was found to have high aYnity for serotonin receptors. Subsequently, heterogeneity was revealed in the 5-HT1 receptor class; 5-HT1A receptors could be distinguished from 5-HT1B receptors (equivalent to the human 5-HT1D receptor) by the high aYnity of the former for spiperone (Pedigo et al., 1981). The use of receptor autoradiographic 114 SODHI AND SANDERS-BUSH techniques demonstrated the existence of a third 5-HT1 receptor in the porcine choroid plexus, the 5-HT1C subtype (later renamed 5-HT2C), through its high aYnity for [3H]mesulergine and [3H]5-HT (Pazos et al., 1984). The application of molecular cloning techniques in the late 1980s revolutionized protein discovery and to date, 14 distinct subtypes of mammalian serotonin receptors have been cloned. Both molecular structure and pharmacological properties determine their classification, and under a revised system, the serotonin receptors are now allocated to seven distinct families (Hoyer et al., 1994). The characteristics and distributions of the diVerent subtypes of serotonin receptors are summarized in Table I. A detailed review of their pharmacology has been compiled by Barnes and Sharp (1999).

A. Distribution and Projections of the Serotonergic System

Serotonergic neurons are part of one of the most widely distributed neuronal systems in the mammalian brain; this neuronal network is also one of the earliest to develop in the embryo. Serotonin-containing neurons projecting to the forebrain originate in four brain stem nuclei, the principal of these being median and dorsal raphe nuclei. The dorsal raphe nucleus projects thin serotonin fibers, which are more abundant in the cortex, whereas the median raphe nucleus provides thick serotonin fibers with large varicosities that are relatively sparse and more abundant in the hippocampus (Kosofsky and Molliver, 1987). The hippocampus re- ceives fibers following a dorsomedial course through the cingulate cortex (reviewed by Rubenstein, 1998). During development of the cortex, the cortical regions have diVerent profiles for the maturation of serotonin axon terminals (D’Amato et al., 1987; DeFelipe et al., 1991). The thick and thin serotonin fiber systems innervate the cortex in diVerent time frames (Vu and Tork, 1992). Because the fibers also change after injury and according to the target cell innervated, classification according to the thickness of the fibers is not consistent (Azmitia, 1999). Serotonin neurons innervate almost all areas of the brain ( Jacobs and Azmitia, 1992), and their projections and targets are summarized in Fig. 1.

III. The Role of Serotonin in Developmental Plasticity

A central tenet of neuroscience is that synaptic plasticity underlies behavioral plasticity and that information is coded by alterations in synaptic strength and connectivity in networks of neurons (Kandel and Spencer, 1968; Martin et al., 2000). Prior to its vital role as a neurotransmitter in adult brain, serotonin acts as a regulator of brain development. The latter is inextricably linked to the TABLE I The Serotonin Receptorsa

Structure Second Principal Effect of Clinical effects of Receptor (genetic locus) messenger distribution receptor activation receptor activation

The 5-HT1 family 5-HT1A 7 TMD, G-protein-coupled Hippocampus, lateral septum, # 5-HT release Anxiolytic and antidepressant, intronless # adenylate cingulate and entorrhinal " ACh release in e.g., buspirone, pindolol, (5q11.2-q13) cyclase cortices, dorsal and median septohippocampal neurons 5-HT syndrome, raphe nuclei " NE release in hypothalamus, hypothermia, hyperphagia, and hippocampus, frontal altered sexual behavior cortex VTA # Glutamate release " Prolactin release,

115 " growth hormone, " ACTH release 5-HT1B 7 TMD, G-protein-coupled Basal ganglia, especially # 5-HT release Hypophagia, hypothermia, (previously intronless # adenylate substantia nigra, globus # ACh release myoclonic jerks, 5-HT1D ) (6q13) cyclase pallidus, ventral pallidum, antiaggressive properties, and entopeduncular nucleus penile erection 5-HT1D 7 TMD, G-protein-coupled # Basal ganglia, especially " GABA release? (previously intronless adenylate cyclase substantia nigra, globus # 5-HT release 5-HT1D´ ) (1p34.3-36.3) pallidus, caudate putamen, # ACh release? periaquaductal grey, hippocampus, cortex, olfactory cortex, dorsal raphe nucleus, locus coeruleus, and spinal cord 5-HT1E 7 TMD, G-protein-coupled Cortex including entorrhinal intronless # adenylate cortex, basal ganglia, (6q14-15) cyclase claustrum, hippocampus (subiculum), amygdale, hypothalamus

(Continued ) TABLE I (Continued ) Structure Second Principal Effect of Clinical effects of Receptor (genetic locus) messenger distribution receptor activation receptor activation

5-HT1F 7 TMD, G-protein-coupled Cortex, especially cingulate and Relief of migraine? intronless # adenylate entorrhinal cortices, hippocampus (3q1) cyclase (CA1-CA3 layers), basal ganglia, claustrum, caudate nucleus, dorsal raphe nucleus The 5-HT2 family 5-HT2A 7 TMD, G-protein-coupled Olfactory bulb, hippocampus, Excitation of 5-HT neurons Antipsychotic (antagonist), 2 introns within " phospholipase C cortex (neocortex, claustrum, Inhibition of NE neurons anxiolytic (antagonist), relief

116 ORF (13q14-21) pyriform and entorhinal cortices), in locus coeruleus of sleep and eating disorders, caudate nucleus, and nucleus # NE release in hippocampus relief of migraine, accumbens " BDNF expression? " cortisol, hallucinogenic, hyperthermia " ACTH, " renin, " prolactin 5-HT2B 7 TMD, G-protein-coupled Cerebellum, lateral septum, Mediation of mitogenic effects Anxiolysis (antagonist)? 2 introns within " phospholipase C dorsal hippocampus and of 5-HT during neural ORF (2q36.3-37.1) medial amygdala, stomach development? fundus, heart 5-HT2C 7 TMD, 3 introns G-protein-coupled Choroid plexusolfactory nucleus, Excitation of 5-HT neurons Antipsychotic (antagonist), (previously within ORF " phospholipase C pyriform, cingulate and # NE and DA release in anxiolytic (antagonist), 5-HT1C ) (Xq24) retrospinal cortices, nucleus mesocortical/mesolimbic NE and antidepressant, relief of accumbens, hippocampus, DA projections " cortisol, migraine and sleep amygdala, subiculum, " ACTH, " prolactin disorders, hypolocomotion, entorhinal cortex, caudate hypophagia, penile nucleus, substantia nigra pars erection, anticonvulsant compacta, striatum, thalamus, hypothalamus, frontal cortex 5-HT3 Ligand-gated cation " intracellular Hippocampus, amygdale, Fast synaptic Vomiting, relief of migraine channel, several Na+:K+ ratio superficial layers of cerebral transmission in brain (antagonist), anxiolysis introns cortex, limbic and " 5-HT release (antagonist), " cognition (11q23.1-23.2) basal ganglia structures, dorsal # ACh release (antagonist), # locomotion vagal complex in brain stem, " GABA release (antagonist), # reward gastrointestinal tract " CCK release (antagonist), # LTP, " DA release analgesia (antagonist)? Na+:K+ ratio 5-HT4 7 TMD, >5 G-protein-coupled Hippocampus, basal ganglia and " 5-HT release " cognition, anxiolysis and introns " adenylate substantia nigra, atrium, and anxiogenesis (antagonist) (5q31-33) cyclase gastrointestinal tract " ACh release " DA release 5-HT5A 7 TMD, G-protein-coupled Cortex, hippocampus, thalamus, " locomotor activity 1 intron # adenylate cyclase olfactory bulb, hypothalamus, (7q36.1) cerebellum, spinal cord 5-HT5B 7 TMD, G-protein-coupled Hippocampus, medial and lateral 117 1 intron # adenylate cyclase habenula, dorsal raphe nucleus, (2q11-13) olfactory bulb, entorrhinal and pyriform cortices 5-HT6 7 TMD, G-protein-coupled Caudate nucleus, olfactory tubercles, Antipsychotic (antagonist), 2 introns " adenylate cyclase nucleus accumbens, hippocampus, antidepressant (antagonist), (1p36-35) cerebral cortex, striatum, stomach, anxiolysis (antagonist) adrenal glands 5-HT7 7 TMD, G-protein-coupled Thalamus, hypothalamus, Antipsychotic (antagonist), 2 introns " adenylate cyclase hippocampus, cerebral cortex, antidepressant (antagonist), (10q21-24) amygdala anticonvulsant (antagonist)

aReviewed by Barnes and Sharpe (1999) and Crossland (2000). TMD, transmembrane domain; ORF, open reading frame; VTA, ventral tegmental area; NE, norepinepherine/noradrenaline; ACh, acetylcholine; GABA, -aminobutyric acid; CCK, cholescystokinin; DA, dopamine. 118 SODHI AND SANDERS-BUSH

Fig. 1. Serotonergic projections in the human brain, arising from the raphe nuclei. The serotonergic projections innervate sympathetic preganglionic neurons, the sensory glomeruli in olfactory bulb, the intermediate lobe of pituitary, the epithelial cells of choroid plexus, the lateral ventricles, the motor neurons of brainstem, the spinal cord, visual cortex and all regions of cerebral cortex. Other transmitter systems make specialized contacts with serotonergic targets: the dopaminergic neurons in substantia nigra, the noradrenergic neurons in locus coeruleus, pacemaker neurons of the suprachiasmatic nucleus, specialized calbindin GABA interneurons in hippocampus, and pyramidal cortical neurons. Cell types in close proximity to the serotonin fibers include glia, endothelial cells, eppendymal cells in addition to the pineal gland and subcommissural organ. processes of long-term potentiation (LTP, described in Section V,A) and synaptic plasticity. The immature brain is thought to overdevelop, producing excess connections and cells. The redundant inputs are pruned according to their activity levels by apoptotic mechanisms guided by existing chemical systems. Therefore the ‘‘use it or lose it’’ principle states that unused connections are removed. Be- cause serotonin is likely to be present earlier in development than other monoamine transmitter systems and because the turnover rate of serotonin is higher in the immature mammalian brain than at any other period (Hamon and Bourgoin, 1979), serotonin probably plays a key role in this developmental process (reviewed by Whitaker-Azmitia, 2001).

A. Serotonergic Projections during Brain Development

The highest levels of serotonergic activity are detected early in development (Lidov and Molliver, 1982). Serotonergic neurons form a superior and inferior group of immature cells, which have distinct maturational and migration patterns SEROTONIN AND BRAIN DEVELOPMENT 119

(Lidov and Molliver, 1982; Wallace and Lauder, 1983). In both groups, serotonergic neurons form di Verent subsets of cells, and the raphe nuclei from which serotonergic fibers project in the brain all have di Verent origins (Azmitia and Gannon, 1986). In the human, serotonergic neurons can be detected when the embryo is just 5 weeks old (Sundstrom et al., 1993), with rapid growth and multi- plication until the 10th week of gestation (Kontur et al., 1993; Levallois et al., 1997; Shen et al., 1989). After 15 weeks, clustering of the serotonin cell bodies in the raphe nuclei is observed. The synaptic density of biogenic amine systems in the human cerebral cortex doubles from birth to 1 year old, when it reaches a peak value and decreases thereafter to adult levels by the age of 10 (Huttenlocher and Dabholkar, 1997). Similarly, levels of serotonin increase during the first 2 years after birth and then decline to adult levels after the age of 5 (Hedner et al., 1986; Toth and Fekete, 1986). An equivalent time course for the development of the serotonergic system has been observed in the chicken (Kojima et al., 1988) and rodents (Rubenstein, 1998) indicating that these changes are conserved in evolution. The early arrival of the serotonergic system before other monoamines indicates that it may be required to guide the development of other neurotransmitter systems (Benes et al., 2000; Whitaker-Azmitia et al., 1996). The role of serotonin as a developmental signal is discussed in Section III,C. In the rat, axonal projections from the rostral raphe nuclei ascend to the mid- brain and forebrain, whereas those of the caudal nuclei descend to the spinal cord (Wallace and Lauder, 1983). The descending fibers enter the spinal cord by embryonic day 14 (E14) and innervate the preganglionic sympathetic neurons and somatic motor neurons. Here they start to form synapses at E17, with innervation of dorsal horn neurons occurring later. The rostral projections are visible soon after serotonin can be detected in the brain stem. The unbranched fibers grow in the marginal zone as a fascicle in the median forebrain bundle, and by E15 they reach the diencephalon, where they branch out. By E17, medial fibers from the medial forebrain bundle project to the frontal pole of the telencephalon, while lateral fibers project to the hypothalamus and arrive at the rostral end of the brain, some crossing the midline in the supraoptic commissure. There is a simultaneous entry by serotonin fibers into the telencephalon, the majority pass- ing through the diagonal bands of Broca, the septal areas, and then projecting into the cerebral cortex. A small number of serotonin fibers enter through the ganglionic eminences (Rubenstein, 1998). Interestingly, after birth there are non- raphe thalamocortical fibers containing serotonin in the sensory neocortex. Be- cause there is no serotonin synthesis within these neurons, serotonin must be transported to neighboring neurons from adjacent synapses (Lebrand et al., 1996), suggesting that all cells found to contain serotonin may not necessarily manufacture it. This may indicate a mechanism by which serotonin can act as a developmental signal in nonserotonergic cells (discussed in Section III,C). 120 SODHI AND SANDERS-BUSH

B. Growth Factors Influencing the Development of Serotonergic Neurons

Several growth factors that inﬂuence serotonergic development are also important in synaptic plasticity events. These include the astroglial growth factor, S100 , levels of which are increased by serotonin, indicating that serotonergic nerves can stimulate their own growth. Inhibition occurs via serotonergic receptors at the nerve terminals. Serotonin not only regulates the growth and development of its targets, but it is also autoregulatory (Whitaker-Azmitia, 2001). S100 is described in greater detail in the review by Rothermundt, Ponath, and Arolt. The serotonin system regulates its own diVerentiation by sequential activation of the 5-HT1A receptor, brain-derived neurotrophic factor and its receptor trkB (see the review by Guillin and colleagues), CREB, CREM, and ATF-1, among many of the signaling molecules under serotonergic inﬂuence (Herdegen and Leah, 1998). In addition, Petl, an ETS domain transcription factor, is closely associated with developing raphe serotonergic neurons. Other neurotrophins and growth factors control the diVerentiation of serotonergic neurons, including bone morphogenetic protein, and ciliary neurotrophic factor. Furthermore, consensus binding motifs for Petl have been detected in the 50-untranslated regions of the human and mouse genes for the 5-HT1A receptor, serotonin transporter, aro- matic l-amino acid decarboxylase (dopa decarboxylase), and tryptophan hydroxylase. These play important roles in the biosynthesis and degradation of serotonin from dietary tryptophan, as illustrated in Fig. 2. It follows that Petl may also be critical for the regulation of serotonin levels (Hendricks et al., 1999), which have profound eVects on brain development.

C. The Role of Serotonin as a Growth Factor

The dietary precursor for serotonin, tryptophan, is found across the phylo- genetic spectrum from lower plants to higher mammals. It is therefore an evolu- tionarily ancient chemical. Its chemical structure is shown in Fig. 2. Because tryptophan possesses an indole ring, it is capable of absorbing light and is vitally important for energy production during plant photosynthesis. Tryptophan can also be converted to auxin, which is a plant tropic factor, guiding plant growth and cell diVerentiation (reviewed by Azmitia, 2001). In animals, tryptophan is also the precursor for melatonin, a light-sensitive amine vital for the control of circadian rhythm. It follows that if auxin is a plant growth factor, then derivatives of tryptophan in animals could have similar functions. Serotonin alters the morphology of many mammalian cell types, including skeletal muscle (O’Steen et al., 1967), platelets (Leven et al., 1983), and ﬁbroblasts (Boswell et al., 1992). Once serotonergic terminals have developed in a target SEROTONIN AND BRAIN DEVELOPMENT 121

Fig. 2. A diagram summarizing the proposed signal transduction pathways of 5-HT2 receptor subtypes. These receptors belong to the superfamily of G-protein-coupled receptors and are specifically linked to the Gq protein, which activates phopholipase C (PLC) when stimulated by the receptor-agonist complex. This initiates the phosphoinositol second messenger cascade, producing inositol triphosphate (IP3) and diacylglycerol (DAG), which stimulate the release of calcium from intracellular stores and the activation of protein kinase C (PKC). Receptors with similar activity include the cholinergic muscarinic, metabotropic glutamate, and 2-adrenergic receptors. The

5-HT2C and M1 receptors may play a major role in the regulation of synaptic plasticity, since both receptors increase the mobilization of calcium ions (Ca2þ) from intracellular stores via PLC activation, which then activates Ca2þ/calmodulin, which opens L-type Ca2þ channels, leading to plastic events. region, serotonin release may influence neurogenesis (Lauder and Krebs, 1976, 1978), neuronal removal through apoptotic mechanisms, dendritic refinement, cell migration, and synaptic plasticity (Chubakov et al., 1986, 1993; Lauder, 1990; Lauder et al., 1981). When these events are combined, they could produce the highly sophisticated organization of the hippocampus or the somatosensory maps called ‘‘barrel fields’’ (discussed in Section III,E,2). At a later developmental stage, serotonin directs dendritic growth. Serotonin activity alters the overall length of dendrites, the formation of dendritic spines, and branches into the hippocampus and cortex (Faber and Haring, 1999; Mazer et al., 1997; Okado et al., 1993; Wilson et al., 1998; Yan et al., 1997a). As the animal matures, 122 SODHI AND SANDERS-BUSH

Fig. 3. L-tryptophan is a dietary precursor of brain serotonin. Serotonin synthesis occurs as summarized above in the postganglionic serotonergic neurons. increased serotonin levels inhibit normal spine formation, perhaps by a 5-HT1A receptor-induced mechanism indicated in Fig. 3 (discussed in Section III,D,1). Depletion of serotonin levels during the developmental years may cause a loss of synapses, which can be corrected by adulthood. However, in the aged animal this may lead to an increase in the number of synapses, a ‘‘reactive synaptogenesis,’’ or perhaps a retention of synapses normally lost (Whitaker-Azmitia, 2001). Therefore, early developmental disturbance has the potential to alter brain structure and repair much later in life. SEROTONIN AND BRAIN DEVELOPMENT 123

Studies of neurotoxin-induced serotonergic lesions of dorsal and medial raphe nuclei have detected changes in cell growth in basal ganglia regions and hypothalamic nuclei of adult rats. Newly generated granule cells can be identified by immunostaining for bromo-2 0-deoxyuridine (BrdU) and the polysialylated form of neural cell adhesion molecule (PSA-NCAM). Decreases in PSA-NCAM staining have been observed after the inhibition of serotonin synthesis induced by parachlorophenylalanine (PCPA) administration, suggesting that serotonin may reduce adhesion by acting on PSA-NCAM expression in its environment and thus facilitate plasticity in adult brain. A normalization of PSA-NCAM staining two months after neurotoxin lesions has been associated with a partial restoration in serotonin fiber density in the nucleus accumbens and the supraoptic nucleus, indicating that PSA-NCAM may facilitate the sprouting of serotonin fibers. As no changes in striatal PSA-NCAM staining have been observed after selective lesions of the dopaminergic pathway, serotonin appears to have a selective and critical role in adult brain plasticity (Brezun and Daszuta, 1999). Prenatal depletion of serotonin delays the onset of neurogenesis in serotonergic target regions. In the fetus evidence suggests that serotonin promotes the di- Verentiation of cortical and hippocampal neurons. In the adult brain, studies indicate that serotonin may play a role in neuronal plasticity by maintaining the synaptic connections in the cortex and hippocampus (Azmitia et al., 1995; Chen et al., 1994; Mazer et al., 1997). Neuronal precursor cells persist in adulthood in two discrete regions, the subventricular zone and the hippocampal subgranular zone, as demonstrated in primates (Gould et al., 1998). Both inhibition of serotonin synthesis and selective lesions of serotonergic neurons are associated with decreases in the number of newly generated cells in the dentate gyrus, as well as in the subventricular zone (Brezun and Daszuta, 1999). Serotonin depletion studies are discussed in more detail in Section IV,A. In the periphery, serotonin has been shown to potentiate the mitogenic eVects of platelet-derived growth factor BB (Eddahibi et al., 1999). The mechanism for these eVects on morphology and cell proliferation could involve the phosphorylation of guanidine triphosphatase-activating protein, which is required for signal in smooth muscle cell mitogenesis induced by serotonin (Lee et al., 1997). Seroto- nergic activity also targets the cytoskeleton by inducing actin polymerization in addition to the regulation and maintenance of microtubules and microfilaments. The mechanism by which serotonin influences this growth is thought to involve the expression of S100 , a neurotrophic factor derived from astroglial cells. S100 is released from glial cells after the activation of glial 5-HT1A receptors. S100 activity increases synaptic stability and promotes neuronal development (reviewed in the chapter by Rothermundt and colleagues). Interestingly, expression of the microtubule-associated protein tau is decreased in undiVerentiated neuroblastoma cells by high levels of serotonin, whereas low serotonin levels increased tau expression ( John et al., 1991). Alterations in tau phosphorylation 124 SODHI AND SANDERS-BUSH induced by serotonin have been linked with the neuropathology of Alzheimer’s disease and other forms of neurodegeneration (Gudelsky and Yamamoto, 2003; Doraiswamy, 2003; Kovacs et al., 2003; Satoh et al., 1992; Yang and Schmitt, 2001).

D. S erotonin Receptorsand D evelopmental P lasticity

Several studies have demonstrated ﬂuctuations in the expression of serotonin receptor subtypes during brain development. In early developmental stages of the neocortex, the transient overexpression of these receptor subtypes has been demonstrated by autoradiography (Bar-Peled et al., 1991a; Dyck and Cynader, 1993a; Leslie et al., 1992; Lidow and Rakic, 1992). As outlined previously in Section III,C, accumulating data suggest that serotonin acts as a developmental signal for brain stem serotonin neurons and their target cells through the activation of serotonin receptors. Serotonin may act presynaptically by generating cAMP, which modulates hyperpolarization-activated cation channels (Ih channels) in axons. Compounds increasing intracellular cyclic adenosine monophosphate (cAMP) mimic and potentiate serotonin action (Dixon and Atwood, 1989; Enyeart, 1981), whereas adenyl cyclase inhibition reduces the serotonergic enhancement of synapse transmission (Dixon and Atwood, 1989). This modulaton increases synaptic strength and could be a mechanism by which serotonin regulates synaptic plasticity (Beaumont and Zucker, 2000). Table I summarizes the distribution and activity of the serotonin receptors, whereas Fig. 4 outlines the adaptive eVects of environmental challenges mediated by serotonin. The involvement of speciﬁc serotonin receptors in synaptic plasticity events is outlined next.

1. The Influence of the 5-HT1A Receptor on Synaptic Plasticity

Evidence suggests that the 5-HT1A receptor is present early in development and is involved in the regulation of serotonergic system development (Bar-Peled et al., 1991a; Hillion et al., 1993). Experiments on pregnant rats have demonstrated that in utero exposure to PCPA, which depletes serotonin in rat brain (Lauder et al., 1985; Sanders-Bush et al., 1972a,b, 1974), reduces the postnatal expression of 5-HT1A receptors, suggesting that the system is autoregulatory (Lauder et al., 2000). 5-HT1A receptors are likely to be functional before birth because they can be up- or downregulated in fetal brain (Lauder et al., 2000; Whitaker-Azmitia et al., 1990). In human fetal brain, 5-HT1A mRNA expression peaks between 16 and 22 weeks (Bar-Peled et al., 1991a). Investigations in several brain regions demonstrate that the highest level of 5-HT1A mRNA expression occurs during the development of that region and declines after maturation has occurred. This phenomenon has been reported in the brain stem (Hillion et al., SEROTONIN AND BRAIN DEVELOPMENT 125

1993), cerebellum (Daval et al., 1987), and visual cortex (Dyck and Cynader, 1993a). The 5-HT1A receptor is expressed at high density in the dentate gyrus. Evi- dence indicates that this receptor is involved in the development of dentate granule cells, and it is probable that it also plays a role in maintaining synaptic integrity in the adult. The 5-HT1A receptor has also been detected on glial cells, and its activation reduces the immunoreactivity of S100 in the dentate area of adult rats, indicating that loss of synapses is due to less neurotrophic activity. In a study performed by Wilson et al. (1998), decreased serotonin in the hippocampus produced a reduction of synaptic density in the dentate molecular layer, which was attributed to lower levels of S100 reductions by astrocytic 5-HT1A receptors (Wilson et al., 1998). In addition to eVects in the hippocampus, amygdala, and cortex, the serotonergic raphe neurons are thought to provide important modulatory eVects on motor output systems. Developmental increases in serotonergic innervation of the rat hypoglossal nucleus, which coincide with decreased 5-HT1A receptor expression by hypoglossal motor neurons (HMs), have been detected. After-spike hyperpolarization inhibition by serotonin on neonatal HMs is lost in juvenile HMs, probably due to 5-HT1A receptor activity. Therefore, 5-HT1A receptor regulation of neonatal HM function is lost in the adult (Bayliss et al., 1997). HMs contribute to innervation of the tongue muscles and to the maintenance of upper airway patency during respiration, which is important in the prevention of obstructive apneas during REM sleep (Remmers, 1990).

2. The Role of 5-HT2 Receptors in the Modulation of Plasticity In addition to the strong evidence supporting a developmental role for 5-HT1A receptors, similar data have been unearthed in investigations of 5-HT2 receptor subtypes. As with 5-HT1A receptor, the activity of 5-HT2 receptors is increased at critical stages of brain development. When 5-HT2R-mediated inositol phosphate levels have been measured, they are approximately 10-fold higher in developing brain compared with mature adult brain (Claustre et al., 1988). An- other similarity with 5-HT1A receptor is that pre- or postnatal environmental stressors acting via the glutamatergic system during development can alter the number and function of 5-HT2 receptors permanently (Aghajanian and Marek, 1999; Meaney et al., 1994; Peters, 1988). Furthermore, pharmacological studies by Niitsu and colleagues (1995) suggest that 5-HT2A receptor activity regulates synaptogenesis in the embryo. In the mouse, serotonin modulates embryogenesis in a dose-dependent manner by the activation of 5-HT2 receptors (Choi et al., 1997, 1998; Moiseiwitsch and Lauder, 1995, 1997; Moiseiwitsch et al., 1998; Shuey et al., 1992, 1993; Yavarone et al., 1993). Lauder and colleagues (2000) investigated expression patterns of 5-HT2 receptors during mouse embryogenesis. DiVerential 126 SODHI AND SANDERS-BUSH and overlapping spatiotemporal patterns of 5-HT2A, 5-HT2B, and 5-HT2C receptor immunoreactivity were observed during active phases of morphogenesis in a variety of embryonic tissues, including neuroepithelia of brain and spinal cord, notochord, somites, cranial neural crest, craniofacial mesenchyme and epi- thelia, heart myocardium and endocardial cushions, tooth germs, whisker fol- licles, cartilage, and striated muscle. Exposure of mouse embryos at the head fold stage to selective 5-HT2 receptor antagonists revealed potent developmental eVects. The most pronounced eVect was observed after the administration of ritanserin, which has high aYnity for all the 5-HT2 receptors, especially the 5-HT2B receptor subtype, and produced 100% malformed embryos. The 5-HT2A/2C receptor antagonist mianserin was 10-fold less potent, whereas ketanserin, which primarily targets 5-HT2A receptor, did not cause a signiﬁcant number of malformed embroys at any dose tested (Lambert and Lauder, 1999; Lauder, 2000). These data support previous evidence that serotonin acts as an important morphoregulatory signal during embryogenesis. As indicated in Table I and Fig. 4, 5-HT2A receptor and 5-HT2C receptor couple to the phosphoinositide (PI) hydrolysis signal transduction pathway. In 1995, Ike and colleagues demonstrated that during development a switch occurs in the functional 5-HT receptor in the rat hippocampus, from 5-HT2A to 5-HT2C, between the ﬁrst and third weeks of life. 5-HT2A receptor antagonists blocked serotonin-induced PI hydrolysis in the hippocampus of 7-day-old rats

Fig. 4. Schematic diagram illustrating the eVects of stress and synaptic plasticity on behavior. This scheme focuses on the role of serotonin. Excitatory amino acids, glucocorticoids, and brain- derived neurotrophic factor (BDNF) are the topics of other articles in this issue. SEROTONIN AND BRAIN DEVELOPMENT 127 but not in 21-day-old rats. In contrast, nonselective 5-HT2A/2C receptor antagonists blocked serotonin-mediated PI hydrolysis in both 7- and 21-day-old rats. These data support the idea that the serotonin-induced PI hydrolysis signalling in the hippocampus of 7-day-old rats is mediated predominantly by 5-HT2A receptor, but in 21-day-old rats the PI hydrolysis signal is mediated mainly by 5-HT2C receptor.Becausetherewasnoconcurrentchangeinthegeneexpression, developmental changes in receptor density were ruled out as a mechanism for the observed di Verences, but instead the explanation probably lies in altered receptor activation. Therefore, 5-HT2A receptor predominates in neonatal hippocampus, whereas 5-HT2C receptor prevails as development progresses (Ike et al., 1995). 5-HT2A receptor promotes neuronal firing by potentiating the activity of AMPA receptors and also by increasing intracellular calcium levels (Fig. 4), which increase the metabolic activity of the cell. There is enhanced glucogenesis, pro- moting cell proliferation. During development, 5-HT2A receptor has been localized to the neural folds, where intense cell growth occurs. Increased intracellular calcium concentration due to 5-HT2A receptor activation also stimulates protein kinase C (PKC) and increases the expression of several transcription factors. These include the immediate early gene, c-fos, and it is also coupled to the Jak/STAT pathway. The latter regulates the expression of myogenic genes and the glucose transporter GLUT3 in cultured skeletal myoblasts (Broydell et al., 1997). 5-HT2A receptors and 5-HT2C receptors also mediate the mitogenic e Vects for serotonin when expressed at high density in fibroblasts ( Julius et al., 1989, 1990). Therefore, the activation of 5-HT2 receptors influences apoptosis and cell growth and perhaps apoptotic mechanisms. 5-HT2A receptor has also been shown to influence postnatal development in the prefrontal cortex (PFC). This region of the brain comprises a large portion of the frontal lobe and undergoes progressive growth in mammals, reaching its greatest development in humans (Rakic and Goldman-Rakic, 1982). Functional studies have demonstrated that PFC plays a key role in cognitive functions (Fuster, 1991; Goldman-Rakic, 1987, 1995) and that PFC damage causes deficits in memory (Kolb, 1984) and in the organization of future events (Fuster, 1985). Dysfunction of the PFC is thought to influence many CNS disorders, particularly in schizophrenia (discussed in Section V,E), as deficiencies in cognition and working memory are prominent symptoms in the disease (Goldman-Rakic, 1994; Weinberger and Berman, 1996). A critical developmental period for the neocortex in rodents occurs during the first 2 postnatal weeks, which is also a period of intense synaptogenesis, as synaptic density increases fivefold between P10 and P15 when it is almost at the level of adult brain (Micheva and Beaulieu, 1996). Neuronal activity plays a critical role during this time, and disruption during development produces enduring changes in cortical circuitry. The strong excitatory eVect produced by serotonin during this period is modulated mainly by 5-HT2A receptors and perhaps 5-HT7 receptors (Zhang, 2003). 128 SODHI AND SANDERS-BUSH

Cytoarchitecture is also altered in the presence of 5-HT2A receptor antagonists by modulating expression of the activity-regulated, cytoskeleton-associated protein (ARC). ARC is an e Vector immediate early gene localized mainly in neuronal dendrites. Elevation of brain serotonin has been shown to increase the abundance of ARC mRNA abundance in the cingulate, orbital, frontal, and parietal cortices, as well as in the striatum, but conversely, produces a reduction in the CA1 region of the hippocampus. Pretreatment with a 5-HT2A receptor antagonist signiﬁcantly attenuates this e Vect in the cortex. However, this attenuation is only partial and is absent in the CA1 region (Pei et al., 2000). Furthermore, administration of a single dose of lysergic acid diethylamide (LSD), which is a hallucinogen and 5-HT2 receptor agonist, has been shown to increase ARC expression in the cortex (Nichols and Sanders-Bush, 2002). The 5-HT2 receptor agonist DOI also stimulate a dose-dependent increase in ARC mRNA abundance in cortical areas, but has much weaker e Vects on ARC mRNA in the striatum and no signiﬁcant e Vects in the CA1, CA3, and the dentate gyrus (DG) of the hippocampus. This DOI e Vect was completely blocked by ketanserin, indicating that it is mediated by 5-HT2A receptor (Pei et al., 2000). Astroglial cell growth is also modulated by 5-HT2 receptor activity. Several glial and glioma cell lines have been shown to express these receptors (Brismar, 1995; Ding et al., 1993; Hirst et al., 1998; Merzak et al., 1996; Wu et al., 1999). The serotonin-induced cell turnover in primary cultures of astroglia from the cortex, striatum, hippocampus, and brain stem is blocked by 5-HT2A receptor antagonists. Moreover, glioma cell migration and invasion can be modulated by serotonin (Merzak et al., 1996). Therefore, the role of serotonin as a growth factor in neurogenesis and synaptic plasticity is mediated in part by the activity of 5-HT2 receptors, and evidence that these processes may be impaired in psychiatric disorders is discussed in Sections V,D and V,E.

IV. Manipulation of the Serotonergic System Alters Synaptic Plasticity

The role of the serotonergic system has been tested in a variety of ways. The creation of lesions within serotonergic circuits alters transmission, as does reduc- ing the production of the neurotransmitter and its precursors, by dietary tryptophan depletion. Conversely, inhibition of sensory or motor activity and investigations into the subsequent alterations in brain structure have provided insight into the serotonergic mechanisms involved in synaptic plasticity. This section discusses data from studies involving the manipulation of serotonergic activity. SEROTONIN AND BRAIN DEVELOPMENT 129

A. Tryptophanand S erotonin D epletion S tudies

Studies of serotonin depletion in rats using PCPA, a tryptophan hydroxylase inhibitor (Koe and Weissman, 1966), found that there was an increase in inducible nitric oxide synthase in the corpus callosum 2–5 weeks after treatment. In addition, neuronal nitric oxide synthase was increased in the striatum and hippocampus, demonstrating a close interaction between nitrergic and serotonergic systems during development (Ramos et al., 2002). PCPA depletion studies have alsoshownthatthedensityofCA1spinesinthehippocampusandthedorsalraphe´ nucleus are maintained by serotonergic projections to these regions (Alves et al., 2002). The importance of serotonin in synaptic plasticity during development and in the maintenance of synapses in the adult has also been demonstrated in similar studies of chicken spinal cord (Okado et al., 1993). The role of serotonin in synaptic plasticity is underscored by the strong relationship between serotonin, S100 , growth-associated protein-43 (GAP-43), and nitric oxide signaling. The latter increases cyclic guanidine monophosphate (cGMP) through guanyl cyclase activation(SouthamandGarthwaite,1993).Nitricoxideactivityisthoughttoplay acriticalroleinsynaptic plasticity andmammalian brain development(Dinerman et al., 1994; Kandel and O’Dell, 1992; Roskams et al., 1994). Long-term depletion of serotonin was modeled in adult rats by the administration of PCPA for 1 week and was shown to increase binding at (S)-[3H] -amino-3- hydroxy-5-methylisoxazol-4-proprionic acid receptors (AMPAr) in the cerebral cortex. In contrast, N-methyl- d-aspartate receptor (NMDAr) binding remained constant (Shutoh et al., 2000). Moreover, the maturation of motor neurons has been investigated in rats injected with PCPA in the lumbar region after birth. Pos- tural dysfunctions were observed, including reduced flexion of the knee and ankle and reduced extension of the hip, probably due to arrested development of these neurons(Pfliegeretal.,2002).Insimilarexperiments,adultratshavebeenshownto produce an elevated glial expression of S100 , lowered serotonin levels, reduced densities of serotonin transporter (SERT), neurofilament-200 and -68 fibers (NF- 200 and NF-68, respectively), and altered cytoskeletal morphology. Even when serotonin levels normalize after treatment, cytoskeletal changes are still present in the striatum, whereas NF-200, NF-68, and SERT levels increased gradually (Ramos et al., 2000). These studies using PCPA demonstrate that serotonin appears to modulate synaptic plasticity by regulating AMPAr density and S100 release. An alternative method of depleting serotonergic transmission is through the control of tryptophan intake, which has been performed in rodents and in clinical studies (Section V,D). Tryptophan-restricted diets in rats produce increased glutamic acid decarboxylase (GAD) activity in the hippocampus and cerebral cortex between age 14 and 60 days. In contrast, -aminobutyric acid (GABA) activity decreases in these regions postnatally, but then increases in rats between 30 and 60 days of age. Reduced GABAergic inhibition by depletion in GABAergic 130 SODHI AND SANDERS-BUSH cells at this stage of development would result in enhanced serotonergic transmission and glutamic acid decarboxylase (GAD) activity (Del Angel-Meza et al., 2002). In the pyramidal neurons of the prefrontal cortex, long-term plastic changes are observed in response to tryptophan depletion during development. At 40 days of age, rats have less profuse dendritic aborization and dendritic processes are enlarged, with an increased number of dendritic spines at 60 days (Gonzalez-Burgos et al., 1996). Additionally, reduced serotonin release is observed in prenatally malnourished anesthetized rats compared with well-nourished rats after electrical stimulation of the median raphe´ nucleus. However, the basal release of serotonin is higher before electrical stimulation in the malnourished group, perhaps due to the reduced density of serotonergic neurons leading to a decreased control of serotonin release. Electrical stimulation of the median raphe´ nucleus in the malnourished group would therefore enhance the inhibition of serotonin release through the negative feedback mechanisms controlled by 5-HT1A and 5-HT1D autoreceptors (Mokler et al., 1999). These changes in neurotransmitter function have important implications for cognitive processes, such as learning and memory (Section V,A), as tryptophan depletion has been shown to impair spatial learning, which is attributed to hippocampal function. In contrast, short-term memory is improved due to serotonergic activity in the prefrontal cortex (Gonzalez-Burgos et al., 1996). These findings are consistent with reports that agonists for 5-HT receptors and GABA receptors impair memory retention, whereas antagonists improve it (Farr et al., 2000). The clinical consequences of depletions in tryptophan intake or reduced serotonin levels in the brain are outlined in Section V,D.

B. Experimental Models of Synaptic Plasticity

1. The Visual Cortex The mammalian visual cortex is comparatively straightforward to manipulate and therefore has been used as a model of postnatal synaptic plasticity. If one eye and not the other is deprived of vision, then permanent impairment to the vision of the deprived eye results, with the reassignment of cortical territory to the other eye. In kittens, this process begins at postnatal day 21 (P21), peaks after 4 to 6 weeks, and decreases gradually in the subsequent months (Cynader et al., 1980; Hubel and Wiesel, 1970). During this critical developmental period there are transient, regional, laminar, and columnal changes in the distribution of serotonergic aVerents and receptors; increases in 5-HT1A receptor and 5-HT2C receptor densities have been noted, which peak at P30 and P40, respectively, followed by a gradual reduction to adult levels (Dyck and Cynader, 1993b). Inter- estingly, 5-HT2C receptor transient expression is concentrated in columns within the striate cortex during this period. If the eye was removed shortly after birth, SEROTONIN AND BRAIN DEVELOPMENT 131 the 5-HT2C receptor columns were absent, and if the 5-HT2C receptor antagonist mesulergine was administered, visual cortex plasticity was lowered during this critical period (Wang et al., 1997). The importance of this receptor was under- lined when electrophysiological studies of brain slices demonstrated that 5-HT activation of 5-HT2C receptor facilitated LTP or LTD in P60–P80 kittens (Kojic et al., 1997, 2000). It has been demonstrated further that 5-HT2C receptor activity provides a major contribution to LTP in layer 4 (Kojic et al., 2001). These receptors could play a significant role in the regulation of synaptic plasticity, as they increase the mobilization of calcium ions (Ca2+) from intracellular stores via phospholipase C activation (Conn and Sanders-Bush, 1984, 1986a,b, 1987; Conn et al., 1986; Sanders-Bush and Conn, 1986), which is illustrated in Fig. 2. Evidence demonstrates that synaptic plasticity is induced after intracellular Ca2+ concentration rises, perhaps via the activation of NMDA receptors or voltage- dependent Ca2+ channels (Perrier et al., 2002). 2. The Somatosensory Cortex Synaptogenesis, dendritic remodeling, and neurogenesis may all contribute to cortical columnarization. The primary somatosensory cortex (S1) of the rat has been studied extensively because of the segmented ‘‘barrel field’’-checkered patterns on layer IV of S1 when immunostained for serotonin receptors. Each barrel is produced by axons extending to the individual whiskers of the rat, making this an ideal model to test the impact of serotonergic manipulations during brain development and synaptic plasticity. A transient production of serotonergic neurons occurs in the embryo, which may regulate the development of this area. Furthermore, several serotonin receptor subtypes, including 5-HT1B and 5-HT2A, transiently appear in a vibrissae-related pattern in S1 during early postnatal development (Chiaia et al., 1994; D’Amato et al., 1987; Lebrand et al., 1996; Rhoades et al., 1990). Raising serotonin levels in rats by the administration of specific monoamine oxidase A (MAOA) inhibitors leads to an increase in the size of the barrels, with apparent fusing of the adjacent barrels (Kesterson et al., 2002; Vitalis et al., 1998). In addition, MAOA gene knockout mice are devoid of the barrel pattern, which reappears when serotonin synthesis is inhibited (Cases et al., 1996). It has also been postulated that the elevation of cortical serotonin promotes GAP-43 expression before P8 in layer IV of S1. Increasing cortical serotonin leads to accelerated development of GAP-43 axons targeting the septal regions (Kesterson et al., 2002). Conversely, if serotonergic input is reduced, altered barrel patterns are observed and delayed maturation occurs (Bennett-Clarke et al., 1994; Blue et al., 1991; Osterheld-Haas et al., 1994; Persico et al., 2000). Moreover, serotonin transporter gene knockout mice display significantly thinner barrels in the posteromedial barrel subfield layer IV and an absence of barrel patterns in other subfields of S1 (Persico et al., 2001). 132 SODHI AND SANDERS-BUSH

V. Does Dysfunction of Serotonergic Signaling Result in Impaired Brain Development?

We have already described the vastness of the serotonergic system within the brain and its widespread inﬂuence in almost every sphere of mammalian physiology (Section II). Furthermore, we have outlined the role of serotonin in the development of many neurotransmitter pathways and several regions of the brain (Section III). It therefore follows that a malfunctioning serotonergic system could be a contributory factor, if not a primary cause, of some developmental disorders. Synapses are probably the cellular substrate for learning and memory, therefore disruption of the serotonergic processes in brain development would lead to cognitive impairment. There are several behavioral and psychiatric disorders with cognitive dysfunction in which deviations from normal serotonergic activity have been discovered, such as schizophrenia. Addictive substances such as cocaine (Whitaker-Azmitia, 1998), alcohol (Kim et al., 1997; Sari et al., 2001; Tajuddin and Druse, 1993; Zhou et al., 2001), and nicotine (Muneoka et al., 1997) alter serotonin levels. These and similar substances are strongly contraindicated in pregnant women, as many have been shown to impair brain development after prenatal exposure. The serotonergic hypotheses of many psychiatric disorders are underpinned by pharmacological evidence. Many diseases are treated with serotonergic drugs, including those disorders thought to have developmental origins, such as schizophrenia, the aVective disorders, anxiety, and disorders of learning, such as autism and mental retardation. Behavioral problems, such as eating disorders, addiction, and stress-related disorders are also thought to be inﬂuenced by impaired serotonergic acitvity. Drugs are often administered for several weeks before a clinical response is observed, hence it is possible that structural changes are needed to alleviate psychiatric symptoms. The relationship of these disorders with serotonin and synaptic plasticity is discussed in the following sections.

A. The Role of Serotonin in Learning and Memory

Long-term potentiation (LTP) is thought to be the cellular mechanism through which memories are stored in the hippocampus (Teyler and Discenna, 1984). LTP is characterized by a long-term elevation in synaptic eYcacy after a short, high-frequency electrical stimulation of aVerent fibers. Changes in synaptic density and the structure of neurons have been associated with LTP, i.e., LTP induces synaptic plasticity, which has a central role in nearly all models of learning and memory (reviewed by Silva, 2003). The phenomenon was first reported in the perforant path–dentate gyrus synapse (Bliss and Gardner-Medwin, 1973) and has subsequently been detected in many other hippocampal pathways. The formation of new memories is thought to require the hippocampus and SEROTONIN AND BRAIN DEVELOPMENT 133 adjacent medial temporal lobe (including the archicortical hippocampus, entorrhinal, perirhinal, and parahippocampal cortices), but the final storage of memories is probably in a widely distributed neocortical network. Lesion studies have suggested that there is a wide distribution of neocortical memory traces en- coded in the strength of synaptic connections among neurons across large areas of the neocortex (Fries et al., 2003). Although glutamate and GABA receptors play a more major role in learning and memory (Zilles et al., 2000), serotonergic e Vects have also been detected (Beaumont and Zucker, 2000; Klancnik et al., 1991; Mazer et al., 1997; Sarihi et al., 2000, 2003), and the regions implicated in memory storage are richly innervated by the serotonergic system (as described in Section II,A, Fig. 1,andTable I). Serotonin depletion inhibits LTP in the dentate gyrus, indicating a serotonergic modulation of LTP in this region. Also, stimulation of the median raphe´ nucleus has been shown to induce LTP in the dentate gyrus (Klancnik et al., 1991). Furthermore, reversible inactivation of serotonergic projections from the median raphe´ nucleus has been observed to enhance the maintenance of LTP in the dentate gyrus so that consolidation and retrieval but not acquisition of learned behavior occurs (Sarihi et al., 1999). This serotonergic lesion also enhances working memory tested by the Morris water maze (Sarihi et al., 2000). Therefore the median raphe´ nucleus has an inhibitory role in memory consolidation and retrieval in classic conditioning experiments and spatial memory (Sarihi et al., 2003). Developing serotonergic neurons are thought to regulate growth factors for dopamine neurons, a potential mechanism for serotonin and dopamine inter- actions in schizophrenia (Whitaker-Azmitia et al., 1995). Serotonin is required during synaptogenesis: if serotonin is depleted during the critical period for synaptogenesis in developing rats, the result is a decreased density of dendritic and synaptic markers in the brains of the adult animals. These rats show deficits in learning and memory (Matsukawa et al., 1997; Mazer et al., 1997). Serotonin also plays a role in maintenance of the adult brain, as depletion of serotonin results in a loss of synapses (Azmitia, 1999; Okado et al., 2001). Behavioral experiments on 5-HT1A receptor gene knockout mice have demonstrated a deficit in hippocampal-dependent spatial learning and memory tasks, such as the hidden platform version of the Morris water maze, but not in nonspa- tial tasks, such as the visible platform version of the Morris water maze. Absence of paired-pulse inhibition in the CA1 region of the hippocampus has also been reported, resulting in an abnormality in short-term neuroplasticity, although LTP was not impaired (Sarnyai et al., 2000). Similar dissociations between short- term and long-term plasticity have been observed in -calmodulin kinase II ( -CaMKII) knockout mice (Frankland et al., 2001; Glazewski et al., 2000; Waxham et al., 1996) and ataxin-1 knockout mice (Matilla et al., 1998), and it has been suggested that short-term plasticity enables storage of information about the timing of events (Buonomano and Merzenich, 1995). In the basolateral amygdala, 134 SODHI AND SANDERS-BUSH

-adrenergicreceptors( AR)arecolocalizedwith5-HT1A receptorsonexcitatory nerve endings (Cheng et al., 1998; Huang et al., 1996), and when ARs are activated, they induce long-term enhancement of synaptic transmission in these neurons (Huang et al., 1996). Application of serotonin lowers this synaptic transmission. This e Vect was mimicked by a 5-HT1A receptor agonist and blocked by a selective 5-HT1A receptor antagonist. Hence, LTP in the basal amygdala seems to be modulated by 5-HT1A receptor cross talk with ARs (Wang et al., 1999). 5-HT1A receptors also interact with glutamatergic receptors in prefrontal cortical (PFC) neurons. Postsynaptic PFC glutamatergic transmission is altered by serotonin via 5-HT1A receptor activation. This leads to a reduction in AMPA-evoked currents in PFC pyramidal neurons through a CaMKII-mediated mechanism, operated by the activation of protein phosphatase 1 and inhibition of protein kinase A. The 5-HT1A receptor/CaMKII mechanism may regulate the synaptic plasticity of PFC neurons (Cai et al., 2002). These events are crucial for learning and memory and for several forms of synaptic plasticity (Mayford and Kandel, 1999).

B. Autismand S erotonin

Autism is a behavioral disorder of unknown etiology that is four times more common in boys than in girls. Symptoms include repetitive movements, lack of imaginative play, ritualistic behavior, and poor communication, leading to reduced social interaction. Bonding emotionally is limited and there is greater sensitivity to tactile (Ayres and Tickle, 1980) and auditory stimulation (Kientz and Dunn, 1997). The deficit in communication only becomes apparent at age 2, when diagnoses are usually confirmed. It was first recognized that serotonin may be connected with the etiology of autism, when elevated platelet serotonin levels were reported in autistic patients (Boullin et al., 1970, 1971; Ritvo et al., 1970). Since then, neurobiological, pharmacological, and genetic data have added to the hypothesis that dysfunction of the serotonergic system plays a role in the development of autism (Betancur et al., 2002; Cook and Leventhal, 1996; Marazziti et al., 2000). The hypothesis is strengthened by increasing evidence for serotonergic involvement in brain development and the especially rich serotonergic innervation of limbic areas critical for emotional expression and social behavior. Depletion of the serotonin precursor tryptophan (discussed in Section IV, A) has been reported to cause a significant deterioration in autistic patients (Cook and Leventhal, 1996; McDougle et al., 1993), and epidemiological studies detected a high frequency of prenatal exposure to cocaine (Davis et al., 1992)or alcohol (Nanson, 1992), which are both known to alter serotonergic activity. A positron emission tomography (PET) study of male autistic patients detected decreased serotonin synthesis in the cortex and thalamus, although there was an SEROTONIN AND BRAIN DEVELOPMENT 135 increase in the dentate nucleus (Chugani et al., 1997), which could lead to developmental abnormalities. In fact, postmortem studies have found reduced branching of dendrites in CA1 and CA3 hippocampal regions (Raymond et al., 1996), along with reduced hippocampal volumes, suggesting that the cells failed to mature and connections with the cortex may not have fully developed (Aylward et al., 1999). It is possible that the high levels of serotonin detected in autism would create a loss of serotonergic nerve terminals during brain development. This may explain why eVicacious treatments for autism enhance serotonergic transmission (Buitelaar and Willemsen-Swinkels, 2000; McDougle et al., 2000; Posey and McDougle, 2000). Drugs targeting the serotonin transporter (SERT), including the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, venlafaxine, fluvoxamine, and clomipramine, are now widely used to treat autism (Fatemi et al., 1998; Hollander et al., 2000a; Namerow et al., 2003). SSRIs appear to alter many autistic symptoms, including social relatedness. Risperidone, an atypical antipsychotic with strong aYnity for many serotonin receptors, particularly 5-HT2A receptor, is also used frequently to treat autism. Neuroendocrine and behavioral challenge paradigms have found abnormal responses to the increased serotonin levels after the administration of fenfluramine or the serotonin precursor 5-hy- droxytryptophan or the direct 5-HT1B/D receptor agonist sumatriptan. It has been suggested that 5-HT1D receptor supersensitivity may be responsible for the repetitive behaviors exhibited by autistic children (Hollander et al., 2000b). Evidence suggests that autism is a disorder of impaired brain development. The limited pharmacological data available provide circumstantial evidence that impaired serotoninergic activity may contribute to the etiology of this disorder. It is possible that the development of brain regions involved in communication and emotion are arrested by prenatal processes altering synaptic plasticity via a serotonergic mechanism that is triggered by either genetic or environmental factors.

C. The Role of Serotonin in Stress and Anxiety

Serotonin is a chemical mediator of inﬂammation. Its secretion and physiological actions mediate stress and pain, aVecting both immune and nervous system functions through the hypothalamic–pituitary–adrenal (HPA) axis. Sero- tonin receptor dysfunction is well characterized in mental disturbances such as depression and anxiety. Considerable evidence supports the idea that the early postnatal period is a critical time for the establishment of lifelong anxiety-related behavior, which is a component of many psychiatric disorders. Moreover, clinical studies demonstrate that early life stressors, such as divorce or bereavement, increase susceptibility to anxiety and mood disorders in adulthood (Breier, 1989; Bulik et al., 2001; Kendler et al., 1992, 1993, 1996, 2000, 2002a,b; Kessler et al., 1997). 136 SODHI AND SANDERS-BUSH

The mechanism linking stress with abnormal plastic events during brain development is thought to involve 5-HT1A receptor activity (discussed in Section III,D). Chronic stress has been shown to produce specific downregulation of 5-HT1A receptors in the hippocampus ( Lopez et al., 1999; Pare and Tejani-Butt, 1996). This hippocampal deficit may partially explain the cognitive dysfunction observed in patients with aVective disorders. Mice lacking the 5-HT1A receptor gene display increased anxiety in behavioral models such as the open field test or elevated plus maze (Heisler et al., 1998a; Parks et al., 1998; Sarnyai et al., 2000; Sibille et al., 2000), and the anxious phenotype is associated with changes in GABAAR neurotransmission (Olivier et al., 2001). This behavior can be reversed by the selective reinstatement of 5-HT1A expression in the hippocampus and cortex during early postnatal development, but not by reinstatement in the adult or in raphe nuclei at any age (Gross et al., 2002). These data indicate that interrupted postnatal 5-HT1A receptor developmental processes contribute to anxiety behavior in adulthood. Active and passive stress responses have been compared in short (SAL) and long attack latency (LAL) mice, which are genetically selected mouse lines re- sponding aggressively to an opponent in the intermale resident–intruder experi- ment. LAL mice have a characteristic chronic elevation in corticosterone levels and a decreased level of 5-HT1A receptors in the dentate gyrus, hippocampal CA1 region, lateral septum, and frontal cortex, but not in the dorsal raphe nucleus (Korte et al., 1996; van Riel et al., 2002). These findings are consistent with the reduced 5-HT1AR expression in mice exposed to chronic stress and the resultant elevation in glucocorticoid levels (Fernandes et al., 1997; Flugge, 1995; Lopez et al., 1998; McKittrick et al., 1995; Meijer et al., 1997a,b; Watanabe et al., 1993; Wissink et al., 2000). In addition to corticosteroids, sex steroids have been shown to alter behavior and synaptic plasticity. Stress-induced reductions in 5-HT1A receptors in the hippocampus can be renormalized by the administration of androgens (Flugge et al., 1997, 1998). Furthermore, hormone levels are known to alter mood, and there are strong links between estrogens and aVective disorders. Fluctuations in these hormones can cause mood swings, anxiety, or postnatal depression. The aVective symptoms, irritability, and anxiety associated with low estradiol levels in postmenopausal women are alleviated by estrogen replacement ( JoVe and Cohen, 1998; Soares et al., 2001). Furthermore, high levels of estrogens have been shown to increase dendrite growth and synaptic plasticity in the rat hippocampus (Foy et al., 1999; Good et al., 1999; Leranth et al., 2000). As with 5-HT1A receptor activity, estrogens reduce neuronal excitability in the basolateral amygdala (Edwards et al., 1999). Female mice lacking the estrogen receptor (ER ) were shown to be more anxious and to have a lower threshold for the induction of synaptic plasticity in the basolateral amygdala, which coincided with increased 5-HT1A receptor expression in the medial amygdala (Krezel et al., 2001). Thus, SEROTONIN AND BRAIN DEVELOPMENT 137 the serotonin system may influence the steroid hormone control of synaptic plasticity. As described in Section III,D,1, 5-HT1A receptor activity inhibits synaptic plasticity in the amygdala, which is considered to be the sensorimotor interface for conditioned fear. Classic fear conditioning, a paradigm for the study of aversive learning and memory, is thought to depend on the integrity of the amygdala (Fendt and Fanselow, 1999; Rogan and LeDoux, 1996), although there is debate regarding the role of the hippocampus in this response (Maren et al., 1997; Radulovic et al., 1999). Studies either depleting or increasing serotonin have provided evidence for the role of serotonin in fear conditioning (Archer et al., 1982, 1984; Hashimoto et al., 1996; Inoue et al., 1996). A specific role for 5-HT1A receptor activity in this response has been indicated by studies of 5-HT1A receptor antagonists in combination with serotonin reuptake inhibition (Hashimoto et al., 1997). The 5-HT1A receptor agonist 8-OH-DPAT caused a deficit in contextual fear due to postsynaptic 5-HT1A receptor activation in rats. Both responses were blocked by the 5-HT1A receptor antagonist WAY100635. Therefore, postsynaptic 5-HT1A receptor activation has been shown to interfere with learning processes in the acquisition of fear (Stiedl et al., 2000). In addition, PET studies of patients with major depression show decreased 5-HT1A receptor binding in the temporal lobe and in the limbic system (Drevets et al., 1999; Sargent et al., 2000), and 5-HT1A receptor agonists have anxiolytic properties in clinical and animal models (Feighner and Boyer, 1989; Menard and Treit, 1999). Although the 5-HT1A receptor plays an important role in anxiogenic processes, the 5-HT2B/2C receptor agonist m-chlorophenylpiperazine (mCPP) also induces anxiety. mCPP has been shown to reduce novelty-seeking behavior. In a two-box light/dark choice situation, mCPP has been found to decrease the time spent by mice in the lit box and the number of transitions between the light and dark boxes. This behavioral test has been validated for the assessment of novel compounds with anxiolytic or anxiogenic properties. Therefore, activation of 5-HT2C receptor enhances anxiety responses toward novel and aversive places (Griebel et al., 1991; Meert et al., 1997). Immobilization of animals is another stress-inducing behavioral paradigm. Im- mobilization decreases the expression of BDNF mRNA in the rat hippocampus, and this eVect could contribute to the atrophy of hippocampal neurons. Pretreatment with a selective 5-HT2A receptor antagonist significantly blocks the influence of stress on the expression of BDNF mRNA. In contrast, pretreatment with either a selective 5-HT2C or a 5-HT1A receptor antagonist did not influence the stress-induced decrease in levels of BDNF mRNA levels (Vaidya et al., 1999). Furthermore, the inhibitory eVects of stress on the activity of periventricular hypophysial dopaminergic (PHDA) neurons have been shown to be mediated by serotonergic neurons, acting via 5HT2Rs, and this activity leads to an increase in the secretion of -melanocyte- stimulating hormone ( -MSH) (Goudreau et al., 1993). Therefore, behavioral 138 SODHI AND SANDERS-BUSH pharmacological evidence indicates an important role for the serotonergic system, together with steroid hormones, in the etiology for anxiety disorders.

D. Serotonergic Influences on Synaptic Plasticity in Affective Disorders

The catecholamine hypothesis of the aVective disorders was proposed in 1965 based on the observation that the antihypertensive agent reserpine was found to lower the mood of patients (Schildkraut, 1965). This drug depletes catecholamines, therefore it was suggested that depression was caused by a dysfunction in the catecholamine system. Coppen (1967) modified this theory after the eVects of monoamine oxidase inhibitors (MAOI) on serotonin were observed by suggesting that depression was caused by reduced serotonin in the synapse (Fig. 2)(Coppen et al., 1967). However, the delay in patient response to antidepressants after administration (which is also seen in antipsychotic therapy) could not be correlated with the rapid eVects of antidepressant drugs on serotonin levels, and their eYcacy is thought to be related to more long-term changes caused by plastic events under the control of the monoamine transmitter systems (Charney et al., 1981). The monoamines, noradrenaline, serotonin, and dopamine, and their metabolites, 3-methoxy-4-hydroxyphenylglycol (MOPEG), 5-HIAA, and homovanillic acid (HVA), respectively, have been studied extensively in the blood, cerebrospinal fluid (CSF), and postmortem brain of depressed patients. There is a general consensus after many clinical studies that MOPEG in the urine and CSF of depressed patients is reduced by about 25% in comparison with controls and that this shows a cyclic change when manic and depressed states are experienced by bipolar patients ( Johnstone, 1982). In 1976, Asberg and colleagues measured 5-HIAA in the CSF as an index of brain serotonin turnover (Fig. 2) and found a bimodal distribution in depressed patients. It was also observed that the severity of depression increased with decreased 5-HIAA levels in a subgroup of patients who were more prone to violent suicide attempts. Several studies have also measured decreases in HVA levels in depressed patients, but once methodological details were stream- lined, no diVerences in CSF HVA, the dopamine metabolite, were observed between patients and controls. By contrast, more than 20 studies have detected a consistent association between high 5-HIAA levels and suicidal behavior, schizophrenia, personality disorder, and impulse control but not bipolar aVective disorder. A low concentration of 5-HIAA in patients is associated with an increased short-term risk for suicide in patients (reviewed by Asberg, 1997). It has been suggested that abnormalities in receptor sensitivity are present in depressed patients (Charney et al., 1981) and that they fail to make adaptive responses to stress or adverse stimuli due to dysfunctional neural plasticity. Therefore the mechanism of antidepressant action and perhaps the etiology of aVective illnesses may involve the induction of specific plastic changes by serotonergic activation. SEROTONIN AND BRAIN DEVELOPMENT 139

Alterations in levels of serotonin during the postnatal period produce long- lasting changes in brain plasticity, including disruption of the maps of the sensory and visual cortices (Section IV,B), decreased density of dendritic spines (Yan et al., 1997b), and changes in the dentate gyrus (Section IV). One hypothesis has suggested that depression develops as a consequence of the poor availability of dietary tryptophan to the brain, which would reduce the availability of serotonin (Fig. 3). A study of plasma tryptophan in aggressive males found that high tryptophan levels correlated with anxiety (Cleare and Bond, 1995). Other investigations have associated tryptophan with feelings of well-being (Charney et al., 1982; Smith et al., 1997). Eighty to 90% acute depletion of dietary tryptophan has been associated with a lowering of mood in normal females but not in males in one study (Ellenbogen et al., 1996), and depletion of tryptophan has been shown to induce relapse of depression in more than 50% of patients during remission of the disease. This relapse was reversed when tryptophan levels were restored; free plasma tryptophan levels were found to be correlated inversely with depression scores during acute tryptophan depletion (Delgado et al., 1990; Smith et al., 1997). Changes in synaptic plasticity after tryptophan depletion are discussed in Section IV,A, and it is possible that these changes are involved in the etiology and treatment of the aVective disorders. Estrogens and aVective disorders are strongly linked, as described in the previous section, since ﬂuctuations in these hormones may cause mood swings, anxiety, or postnatal depression. High levels of estrogens have been shown to increase dendrite growth and synaptic plasticity in the rat hippocampus (Foy et al., 1999; Good et al., 1999; Leranth et al., 2000). Furthermore, as with 5-HT1A receptor stimulation, estrogens reduce neuronal excitability in the basolateral amygdala (Edwards et al., 1999). Investigations into the mechanisms by which endogenous factors stimulate neurogenesis have determined that serotonin and estradiol act through a common pathway to increase cell proliferation in the adult dentate gyrus. Neurogenesis has also been studied in animal models of depression. Ovariec- tomy is a method of depleting estrogens, creating depressive behavior in rodents. Combining ovariectomy with inhibition of serotonin synthesis using PCPA treatment produced approximately the same decreases in the number of BrdU and PSA-NCAM-immunolabeled cells (indicating a reduction in newly generated cells) in the subgranular layer as ovariectomy alone. Administration of 5-hydro- xytryptophan (5-HTP), a precursor of serotonin (Fig. 3), has been shown to restore cell proliferation decreased primarily by ovariectomy, whereas estradiol does not reverse this change. Estrogen may regulate structural plasticity by stimulating PSA-NCAM expression independently of neurogenesis, as shown by the increases in the number of PSA-NCAM-labeled cells in pregnant rats. These data indicate that positive regulation of cell proliferation and neuroplasticity by serotonin and estrogen may contribute to the reduced hippocampal connectivity observed in depressed patients (Banasr et al., 2001). 140 SODHI AND SANDERS-BUSH

The aVective symptoms of irritability and anxiety, which are associated with low estradiol levels in postmenopausal women, are alleviated by estrogen replacement ( Jo Ve and Cohen, 1998; Soares and Cohen, 2001). Female mice lacking the estrogen receptor (ER ) were shown to be more anxious and to have a lower threshold for the induction of synaptic plasticity in the basolateral amygdala, which coincided with increased 5-HT1A receptor expression in the medial amygdala (Krezel et al., 2001). Together, these studies demonstrate the link between the serotoninergic system and the steroid hormone control of synaptic plasticity in the aVective disorders.

1. Serotonin Receptors and Depression The regulatory actions of serotonin are mediated by serotonin receptors, therefore the distinct temporal expression patterns of serotonin receptors may re- flect their changing roles during development. Serotonin is thought to regulate the production of neurotrophic factors in the CSF. 5-HT2C receptors are present at high density and probably play a role in CSF production. 5-HT2c receptors may mediate these regulatory functions of serotonin (Esterle and Sanders-Bush, 1992). Psychiatric disorders comprise an array of overlapping symptoms, and patients diagnosed with a variety of CNS disorders often su Ver with sleep disturbances. Staner and colleagues (1992) demonstrated that 5-HT2 receptor antagonists produced increased slow wave sleep in healthy individuals, whereas depressed patients exhibited a smaller increase in slow wave sleep at the same dose of drug (Staner et al., 1992). 5-HT2 receptor antagonists have antidepressant potential (Eison, 1990; Marek et al., 1989), which may be related to an interaction with 5-HT1A receptors (Eison, 1990; Yocca et al., 1990). Alterations in 5-HT2A receptor expression and activity have been demonstrated in patients with a range of CNS disorders, and the changes could play a role in the pathogenesis and treatment of psychiatric disease (Burnet et al., 1996, 1999; Eastwood et al., 2001; Harrison and Geddes, 1996; Harrison and Burnet, 1997). An increase in postsynaptic 5-HT2A receptor binding in postmortem brains of patients may reveal a pathophysiological mechanism in aVective disorders (McKeith et al., 1987; Yates et al., 1990). The deficiency of serotonergic activity in depressed patients is thought to increase their vulnerability to the disease. Studies have shown low levels of serotonin in the brains of depressed patients who have committed suicide (Coppen and Doogan, 1988) and that there are altered densities of 5-HT2A receptors in the frontal cortex of suicide victims (Mann et al., 1986a,b,c; Stanley et al., 1986a,b), in depressed patients (McKeith et al., 1987), and in individuals at risk for suicidal behavior (Arango et al., 1997; Audenaert et al., 2001; Pandey et al., 1995, 1997; Stockmeier et al., 1997). Drug treatments for the aVective disorders, for example, antidepressants such as lithium, mianserin, and fluoxetine, are thought to act through the serotonergic system and usually raise serotonin levels. Therefore, it has been proposed that SEROTONIN AND BRAIN DEVELOPMENT 141 there is a decrease in serotonergic activity in the brains of depressed patients, leading to an upregulation of 5-HT2A receptors. Evidence supporting this hypothesis includes the finding that there is increased 5-HT2A receptor-mediated phosphoinositide turnover in the platelets of patients with aVective disorders (Mikuni et al., 1992). Moreover, downregulation of brain 5-HT2 receptors has been demonstrated 2–4 weeks after the administration of many antidepressants (Peroutka and Snyder, 1980), such as lithium (Treiser and Kellar, 1980; Wajda et al., 1986), monoamine oxidase inhibitors (Kellar et al., 1981), some selective serotonin reuptake inhibitors (SSRIs) (Eison et al., 1991; Nelson et al., 1989; Stolz et al., 1983), 5-HT1A receptor partial agonists (Lafaille et al., 1991; Yocca et al., 1991), and clozapine (Hietala et al., 1992). Conversely, electroconvulsive therapy upregulates 5-HT2A receptor-binding sites (Burnet et al., 1996; Kellar et al., 1981). Alterations in 5-HT2A receptor binding also appear to be related to the severity of depressive symptoms, as clinically improved patients have similar densities of 5-HT2A receptors to controls (Yates et al., 1990). This evidence has been confirmed by studies in platelets when patients were treated successfully with antidepressants (Biegon et al., 1990). Raising the level of serotonin in the synapse by the administration of antidepressants produces a cascade of events mediated by 5-HT2, 5-HT1A, 5-HT4, and 5-HT7 receptor subtypes. 5-HT2 receptor stimulation raises intracellular Ca2+ levels and activates CaM kinases, which lead to CREB phosphorylation at ser133. This increases expression of the BDNF gene, which promotes neuronal plasticity and survival. Similarly, 5-HT1A receptor and 5-HT7 receptor stimulation increases Raf, MEK, Erk 1, Erk 2, and Rsk 2 (critical for cell survival), which leads to phosphorylation of the proapoptotic protein BAD and inactivates it. Rsk also activates CREB phosphorylation, conferring cell survival by increasing expression of the antiapoptotic protein Bcl2 (reviewed by D’Sa, 2002; Duman, 2000). Ritanserin, a 5-HT2A receptor antagonist, has been reported to have anxiolytic or antidepressant properties in several studies (Bakish et al., 1993; Bersani et al., 1991; Ceulemans et al., 1985). Nefazodone blocks both noradrenaline and serotonin reuptake in addition to 5-HT2 receptors and has demonstrated antidepressant eYcacy in several controlled trials and was well tolerated by patients (Feighner et al., 1998). Another 5-HT2 receptor antagonist, mirtazapine, has been launched as a treatment for depression. Mirtazapine also acts as an antagonist at 2 and 5-HT3 receptors and this combined activity increases noradrenergic and serotonergic transmission, contributing to its therapeutic eYcacy (de Boer, 1996; de Boer et al., 1996; Dinan, 1996). The atypical antipsychotic drug clozapine has also demonstrated eYcacy in the treatment of depressive symptoms of bipolar aVective disorder, but may exacerbate mania (Frye et al., 1998). Although 5-HT2A receptors have been investigated extensively in studies of mood disorders, there is also evidence implicating altered 5-HT2C receptor function in these illnesses. Molecular genetic studies show that a single nucleotide 142 SODHI AND SANDERS-BUSH polymorphism in the 5-HT2C receptor gene is associated with bipolar aVective disorder (Lerer et al., 2001) and that the locus of the 5-HT2C receptor gene, Xq24, is linked to this disease (Craddock and Jones, 1999, 2001). SSRIs have been shown to have high aYnity for 5-HT2C receptor, and antipsychotic drugs with high 5-HT2C receptor aYnity, such as clozapine, are also indicated for the treatment of bipolar disorder (Calabrese et al., 1991, 1996; Kimmel et al., 1994). Increased 5-HT2C receptor responsiveness accompanies the isolation-rearing model of anxiety/depression and may contribute to the enhanced response to stress and the increased neophobia observed. In isolation-reared rats, rapid downregulation of supersensitive 5-HT2C receptors may occur in the hippocampus following a serotonergic agonist challenge (Fone et al., 1996). 2. The Serotonin Transporter and Antidepressants A major site of action for many antidepressants is the serotonin transporter (SERT). A growing body of evidence indicates that variability in SERT gene expression influences temperamental traits, which could be determined by genetic factors, and may lead to psychopathology. Anxiety, depression, and aggressive behavior are all thought to be alleviated by altered SERT activity, but the mechanism of therapeutic eYcacy of SSRIs is still unclear and animal models provide a valuable tool for investigation. Animal models of depression have been varied, including procedures such as olfactory bulbectomy, maternal deprivation, and clomipramine administration. Dendritic spines could represent an anatomical marker for the enduring changes accompanying depression. Dendritic spines are the postsynaptic sites of most excitatory synapses, and their density increases during the first 2 postnatal months in rat hippocampus. Synaptic development is altered significantly in the hippocampus if there is variation in the levels of serotonin and norepinepherine during this time period. Norrholm and Ouimet (2000) have examined dendritic spine density in the CA1 region of the hippocampus and dentate gyrus of juvenile rats after acute and chronic exposure to antidepressant drugs. Acute antidepressant treatment has been reported to increase dendritic length and spine density, whereas chronic treatment with fluoxetine, a selective serotonin reuptake inhibitor, arrests spine development into young adulthood. Further investigations have revealed that olfactory bulbectomy reduces spine density in CA1, CA3, and dentate gyrus compared to sham-operated controls. Chronic treatment with a non- specific tricyclic antidepressant reverses the bulbectomy-induced reduction in dendritic spine density in CA1, CA3, and dentate gyrus. However, the atypical antidepressant mianserin, with 5-HT2A/2C receptor antagonist properties, only reversed this reduction in dentate gyrus. By contrast, other models of depression do not demonstrate this eVect. Hence enduring changes in hippocampal dendritic spine density could contribute to a neural mechanism specific to this model of depression (Norrholm and Quimet, 2001). SEROTONIN AND BRAIN DEVELOPMENT 143

It has been reported that the projections arising from the hippocampal structures to the hippocampo-medial prefrontal cortex (mPFC) are involved in the exe- cution of higher cognitive functions in rats. The eVects of single and repeated antidepressant treatment on the synaptic eYcacy and synaptic plasticity in the rat medical (mPFC) pathway have been examined using the drug fluvoxamine, a selective serotonin reuptake inhibitor similar to fluoxetine. Fluvoxamine has been reported to enhance synaptic eYcacy in the hippocampo-mPFC pathway in a dose-dependent manner, and repeated treatments enhance synaptic plasticity, so that the establishment of long-term potentiation in the hippocampo-mPFC pathway improves significantly. These findings may indicate the mechanism by which SSRIs produce their therapeutic eVects in depressive disorders (Ohashi et al., 2002). Investigations in mice lacking the SERT gene have demonstrated adaptive changes in 5-HT2A receptor function. Autoradiographic labeling of these receptors by the selective antagonist [3H]MDL 100,907 and saturation experiments with cortical membranes have revealed a new localization of 5-HT2A receptors in the external field of striatum and regional variations in adaptive changes in the density of 5-HT2A receptors in SERT (-/-) mutants: a reduction of 30–40% in the claustrum, cerebral cortex, and lateral striatum when compared to wild-type mice (Rioux et al., 1999). Furthermore, immunohistochemistry of the cerebral cortex of SERT knockout mice has revealed a nearly complete absence of serotonin and of barrels, both at P7 and adulthood. VMAT2 knockout mice, which completely lack an activity-dependent vesicular release of monoamines, including serotonin, also display an absence of serotonin in the cortex but have almost normal barrel fields, albeit with some reduced postnatal growth. These data support the idea that transient SERT expression is required for barrel pattern formation, whereas activity-dependent vesicular serotonin release is not essential for this process (Persico et al., 2001). Although the significance of these observations has yet to be fully explained, the importance of serotonin receptors and SERT in the etiology and treatment of the aVective disorders has been established. The development of depressive illness is reviewed more comprehensively by Lesch (2000, 2001).

E. Altered Synaptic Plasticity in Schizophrenia

1. Is Schizophrenia Caused by Impaired Brain Development? The neurodevelopmental and neurodegeneration hypotheses of schizophrenia have been opposing etiological theories for many decades. The major glitch in the neurodegenerative hypothesis has been the failure to detect gliosis in postmortem schizophrenic brain (reviewed by Harrison, 1995). The alternative, neurodevelopmental hypothesis, proposes dysfunctional brain development and growth during embryogenesis and childhood before the emergence of 144 SODHI AND SANDERS-BUSH schizophrenia during or after adolescence (Weinberger, 1995). Although the neurodevelopmental theory predominates, concurrent neurodegenerative processes that do not involve sustained gliosis have not been excluded (Woods, 1998). The neurodevelopmental hypothesis is supported by findings of delayed developmental milestones in preschizophrenic children, including learning and behavioral abnormalities, indicating abnormal brain function prior to the diagnosis of schizophrenia (Cannon et al., 1997; Chua et al., 1996; Hanson et al., 1976; Jones et al., 1994; Lewis and Levitt, 2002; Marenco et al., 2000; van Os et al., 1995). Murray and colleagues (1992) suggested that the age of disease onset could be used to categorize three forms of schizophrenia: congenital, adult onset, and late onset (Murray et al., 1992). The former can be traced to brain abnormalities during pre- or perinatal stages of development, with gradual increases in behavioral disturbances until the disease can be diagnosed in adolescence or early adulthood. The congenital form is thought to be more common in males (Pilowsky et al., 1993; Stober et al., 1998), whereas the late-onset disorder is more prevalent in females (Hafner, 2003; Palmer et al., 2001). Several neurodevelopmental mechanisms have been proposed. In addition to theories of brain lesions that occur before infancy and lie dormant until adolescence (Weinberger, 1987), it is also possible that a lesion occurs during adolescence before the onset of disease symptoms. Alternatively, computer simulations have proposed a model of schizophrenia in which reduced synaptic connectivity occurs after disturbed neural development during both perinatal and adolescent periods (McGlashan and HoVman, 2000). Alterations in brain structure have been observed in postmortem studies and neuroimaging of schizophrenia subjects. These changes have not been conclu- sive, as there is considerable overlap with the normal range measured in controls. In addition, there are several problems with these studies, including small sample sizes and patient drug history, because antipsychotic drugs have been shown to produce structural changes in the brain (Crow et al., 1986; Meredith et al., 2000). Even so, a consensus has been reached for some neurobiological changes that have been confirmed by several independent studies summarized later. Initially, anatomical research of schizophrenic brain identified enlargements of the lateral and third ventricles in conjunction with a decrease in cortical volume. The latter was particularly prominent in the temporal lobe and medial temporal lobe structures, especially the hippocampal formation and amygdala (Lawrie and Abukmeil, 1998; Wright et al., 2000). Subcortical structures appear to be reduced in size, including some thalamic nuclei (Pakkenberg and Gundersen, 1989; Popken et al., 2000; Young et al., 2000) and the striatum (Keshavan et al., 1998). Reduced normal brain asymmetry is another consistent finding with increased structural variability in the left hemisphere of schizophrenia brains (reviewed by Harrison, 1999b). Considering the early anatomical evidence, Feinberg (1982) proposed that the central pathogenetic process in schizophrenia included altered synaptic pruning SEROTONIN AND BRAIN DEVELOPMENT 145 during adolescence (Feinberg, 1982). A smaller brain volume in schizophrenia could be explained by increased cell death, which would account for the decreased volume of the thalamus (Young et al., 2000), but not the changes in the cortex and hippocampus. These structures do not display cell loss (Pakkenberg, 1993) but instead there are smaller neurons and more densely packed cortical cells (Selemon et al., 1995, 1998; Weinberger, 1999). Altered synaptic plasticity has been inferred by these data, as neuronal cell body size correlates with the extent of dendritic ar- borization (Selemon and Goldman-Rakic, 1999). Moreover, fewer dendritic spines have been observed on cortical and hippocampal pyramidal neurons in schizophrenia subjects (Garey et al., 1998; Glantz et al., 2000; Rosoklija et al., 2000), and a decrease in the number of synapses in the prefrontal cortex and hippocampus in schizophrenia is suggested by the lower abundance of synaptic proteins in these areas (reviewed in the chapter by Eastwood). Altered synaptic plasticity would probably release a cascade of events altering the expression of genes controlling synaptic function, especially during critical developmental periods. Although the jury is still out on the underlying mechanisms surrounding these developmental disturbances, because the serotoninergic system plays such an important role both in neurodevelopment and in the pharmacotherapy of schizophrenia, it is possible that an aberrant serotonin-dependent developmental process contributes to the etiology of the disease. 2. The Serotonergic Hypothesis of Schizophrenia The idea that serotonergic activity contributes to the etiology of schizophrenia evolved from the observation that lysergic acid diethylamide, a drug structurally similar to serotonin, was hallucinogenic (Gaddum and Picarelli 1954; Jacobs et al., 1979; Pieri et al., 1978). Initially there were doubts about the relevance of these findings, because the psychosis induced by LSD involved primarily percep- tual disturbances, i.e., there was a prevalence of visual rather than auditory hallucinations, an absence of thought disorder, and the preservation of aVect and insight, which is only found in a small proportion of patients with schizophrenic psychosis (Szara, 1967). However, these diVerences were minimized when LSD psychosis was compared with the early stages of schizophrenia rather than the chronic illness (Freedman and Chapman, 1973). The LSD psychosis has been found to be a close model for the reality distortion syndrome in schizophrenia but not for the negative symptoms prevalent in a subset of patients (Slade, 1976). Evidence suggests that LSD produces its psychotomimetic eVects through the stimulation of 5-HT2 receptors (Sanders-Bush et al., 1988; Sanders-Bush and Breeding, 1991), and because atypical antipsychotic drugs have high aYnities for these receptors, there is circumstantial pharmacological evidence for the role of serotonin receptors in the development of schizophrenia. The behaviors observed after the administration of serotonin receptor ligands and the distribution of serotonin receptors in brain regions involved in cognition and mood also support this 146 SODHI AND SANDERS-BUSH hypothesis and are summarized in Table I. Also the importance of serotonin in development and neural plasticity has been established in previous sections of this review. Further evidence connecting serotonin with the development of schizophrenia includes the fact that serotonin levels can be altered during viral infections in development (Pletnikov et al., 2000; Popenenkova et al., 1977; Yamashita et al., 1989), malnutrition (Blatt et al., 1994; Kaye et al., 1991; Manjarrez et al., 1996), social isolation (Whitaker-Azmitia et al., 2000), hypoxia (Kim et al., 1994), and stress (Lapiz et al., 2001; Read et al., 2001; Robinson and Becker, 1986) (discussed in Section V,C). Most of these are epidemiological risk factors for schizophrenia later in life (reviewed by Lewis and Levitt, 2002) and are associated with altered brain development in the embryo and early childhood (Miller and Azmitia, 1999). a. Serotonin Receptors and Pharmacological Studies of Schizophrenia. The core symptoms distinguishing schizophrenia from other mental disorders according to DSM IV diagnostic criteria are delusions and hallucinations, which contribute to the loss of insight, which is characteristic of the disease. It is recognized that hallucinations occur after activation of the 5-HT2 receptors because, LSD acts potently at 5-HT2 receptor sites, as do the substituted phenethylamine hallucinogens such as mescaline (Aghajanian, 1994). Moreover, the aYnity of these compounds for 5-HT2 receptor sites has been found to be closely related to their potency as hallucinogens in humans (Glennon et al., 1984; Titeler et al., 1988). Humanstudies ofthepsilocybinindicatethat 5-HT2 receptors areinvolved inhal- lucinogenesis (Vollenweider and Geyer, 2001; Vollenweider et al., 1998). Evidence fromantipsychotic treatment studies also supports theserotonergic hypothesis.Al- though the discovery of antidopaminergic antipsychotic drugs meant that this hypothesis was eclipsed temporarily by the dopamine theory of schizophrenia, interest in serotonin reemerged with the discovery of atypical antipsychotic treatments.Thearchetypeatypicaldrugclozapineisanantipsychoticwithhighe Ycacy in patients exhibiting a poor response to conventional antidopaminergic antipsychotics. Clozapine has been found to have a higher a Ynity for serotonin receptors thanfordopaminereceptors(Meltzeretal.,1989a,b,c).Itisstillundecidedwhether thesepharmacologicalindicationsaresymptomaticorcausalinschizophreniaand therefore biochemical and postmortem studies have been conducted to address this question. The proposed dysfunction in synaptic plasticity in schizophrenia could un- leash a cascade of changes in the expression of genes controlling synaptic function, especially during critical developmental periods. Because serotonin plays a vital role during development (discussed in Sections III and IV), investigations of gene expression in schizophrenia may provide etiological clues. In fact, postmortem studies have found alterations in the abundance of several 5-HTRs. Binding sites for 5-HT1A receptors are increased in the prefrontal cortex, cingulate cortex, and temporal cortex in schizophrenia (Burnet et al., 1996; Gurevich et al., 1997; SEROTONIN AND BRAIN DEVELOPMENT 147

Hashimoto et al., 1991, 1993; Simpson et al., 1996; Sumiyoshi et al., 1996), with no changes in the encoding mRNA (Burnet et al., 1996). Reductions in the abundance of 5-HT2A receptor mRNA have been reported in the prefrontal, cingulate, temporal, and occipital cortices (Burnet et al., 1996; Hernandez et al., 2000), and although there have been some failures to replicate these data, the majority of studies have demonstrated a decrease in 5-HT2A-binding sites in the prefrontal cortex in schizophrenia (reviewed by Harrison and Burnet, 1997; Harrison and Geddes, 1996). Postmortem studies have also demonstrated that the abundance of 5-HT2A receptor is reduced in schizophrenia in brain regions shown to have important neuropathological alterations specific to the disease (reviewed by Harrison, 1999a). Molecular genetic studies have shown associations between single nucleotide polymorphisms (SNPs) in the 5-HT2A receptor gene and schizophrenia (Inayama et al., 1996; Sodhi et al., 1999a; Spurlock et al., 1998; Williams et al., 1996, 1997) and antipsychotic drugs are being increasingly developed to target this receptor (reviewed by Sodhi and Murray, 1997). Because some behavioral responses elicited by acute doses of LSD resemble symptoms of schizophrenia, characterization of gene expression profiles after LSD may provide clues about the etiology of the disease. A small group of genes within the rat prefrontal cortex were found to have altered expression: ania3, ARC, c-fos, I- , krox-20 (erg2), neuron-derived orphan receptor 1(Nor1), and serum glucocorticoid kinase. These findings lend weight to the developmental hypothesis of schizophrenia because many of these proteins alter synaptic plasticity (Nichols and Sanders-Bush, 2002) and the prefrontal cortex is a region associated with neurochemical and structural alteractionsinschizophrenia(Goldman-Rakic,1994;Wein- berger and Berman, 1996), these findings provide support for the developmental hypothesisofschizophrenia(SectionV,E,1).TheresponseofthesegenestoLSDad- ministration was reported to be dynamic with diVering rates of expression changes. ARCwasthe mosthighly expressed gene andwasalsothegenewiththegreatestin- crease in expression after LSD treatment (Nichols et al., 2003). The majority of expression increases were due to activation of 5-HT2A receptor. Furthermore, Pei and colleagues (2000) observed that 5-HT2A receptor antagonists produced cy- toarchitectural changes by modulating the expression of ARC. In another study, LSD administration produced a five- to eightfold increase in fos-like immunoreactivity in the medial prefrontal cortex, anterior cingulate cortex, and central nucleus of amygdala. LSD activation of the medial prefrontal cortex and anterior cingulate cortex was found to be mediated by 5-HT2A receptor, whereas 5-HT2A receptor activation in the amygdala was just a component of the response (Gresch et al., 2002). Although attention has focused on the 5-HT2C receptor subtype, the 5-HT2C receptor subtype may also be relevant, as lysergic acid diethylamide is a high- aYnity agonist at 5-HT2CR (Burris et al., 1991). Furthermore, several genetic studies have detected associations between 5-HT2C receptor cys23ser polymorphism and long-term hospitalization in schizophrenia (Segman et al., 1997), 148 SODHI AND SANDERS-BUSH and between both 5-HT2A receptor and 5-HT2C receptor genes and hallucinations in dementia (Holmes et al., 1998). Variation in both these genes has also been associated with a therapeutic response to clozapine (Arranz et al., 1995, 1996, 1998; Masellis et al., 1995, 1998; Sodhi et al., 1995, 1999b). The importance of 5-HT2C receptor in CNS disorders is also emphasized by the potentially fatal neurological deficits observed in 5-HT2C receptor knockout mice (Tecott et al., 1995). In addition, interesting changes have been detected in 5-HT2C receptor RNA editing, a posttranscriptional process by which 5-HT2C receptor mRNA undergoes editing to produce several receptor variants, some with pharmacological di Verences (Burns et al., 1997). Elevated expression of 5-HT2C receptor mRNA unedited and partially edited isoforms has been detected in the dorsolateral prefrontal cortex of schizophrenia subjects treated with antidopaminergic drugs (Sodhi et al., 2001). Because the unedited 5-HT2C receptor exhibits greater G-protein coupling and constitutive activity (Herrick-Davis et al., 1999; Niswender et al., 1999), reduced RNA editing of the receptor may increase 5-HT2C receptor activity in the dorsolateral prefrontal cortex in schizophrenia. Although the association between 5-HT2c RNA editing and schizophrenia has not been replicated (Dracheva et al., 2003), 5-HT2c RNA editing has been associated with suicide in several studies (Gurevich et al., 2002; Iwamoto and kato, 2003; Niswender et al., 2001). Improved methodology and increased sample numbers will facilitate investigations into this exciting phenomenon. Examination of other serotonin receptors has revealed reductions in hippocampal levels of both 5-HT6 receptor mRNA and 5-HT7 receptor mRNA in the prefrontal cortex in schizophrenia (East et al., 2002a, b). Serotonin also binds to the serotonin transporter, which has also been examined in schizophrenia research because it is well established that ligands for SERT alter mood and SERT antagonists are widely used to treat depressive disorders (Section V, D). Some studies have reported a decreased density of transporter-binding sites in the schizophrenic frontal cortex (Joyce et al., 1993; Laruelle et al., 1993; Ohuoha et al., 1993), although others have reported no change (Dean et al., 1995, 1996; Gurevich and Joyce, 1997). In contrast, SERT mRNA levels appear to be increased in this brain region. However, the drug histories of the psychiatric case and control groups di Ver in postmortem studies and could confound these data (Hernandez et al., 2000). Furthermore, reduced SERT-binding site densities have been observed in the cingulate cortex in schizophrenia, but are increased in striatum ( Joyce et al., 1993). In the hippocampus, no alterations in the density of transporter-binding sites have been found, but a lower aYnity of the transporter for [3H]paroxetine in schizophrenia has been reported (Dean et al., 1995). Therefore, changes in serotonin receptor and SERT gene expression, altered serotonin levels, and behavioral studies provide support for the hypothesis that a dysfunctional serotonergic system alters synaptic plasticity suViciently to cause developmental changes leading to schizophrenia. SEROTONIN AND BRAIN DEVELOPMENT 149

F. Down’s Syndrome,Mental Retardation, and Serotonin

In contrast with disorders such as schizophrenia and autism, Down’s syndrome is associated with reduced levels of serotonin, detected first in blood (Boullin and O’Brien, 1971; Tu and Zellweger, 1965), then in cerebrospinal fluid (Scott et al., 1983), and finally in studies of postmortem brain (Mann et al., 1985). Neurotransmit- ter deficits in Down’s Syndrome are comparable to those found in Alzheimer’sdis- ease (Godridge et al., 1987). In Down’s syndrome, the expected peak of 5-HT1A receptor density during development is greater than in control postmortem brain, but this decreases below controls after birth (Bar-Peled et al., 1991b). This may explain the findings of initial dendritic overdevelopment, followed by hypertrophy (Becker et al., 1986; Takashima et al., 1994). It has been proposed that similar to autism, the serotonergic system fails to mature and form appropriate connections in the brains of Down’s syndrome children (Okado et al., 2001). In Down’ssyndrome adults there is a region-specific increase in serotonin. These increases occur in the frontal and occipital cortices (Gulesserian et al., 2000), while there are reductions in the thalamus, caudate, cerebellum, and temporal cortex (Seidl et al., 1999). Pharmacological evidence supports a serotonergic role in the development of the symptoms of Down’s syndrome, as serotonergic drugs are especially useful in the treatment of the aggressive symptoms, self-harm, cognitive impairment, and depression exhibited by patients (Gedye, 1990, 1991). Interestingly, the gene for S100 is located on chromosome 21, which is in trisomy in Down’ssyndrome(Ueda et al., 1994a,b). Overexpression of the S100 protein has been detected in postmortem brain and lymphocytes of Down’s syndrome patients, prenatally and in adults (Kato et al., 1990). S100 produced by astrocytes is used as a trophic factor by serotonergic neurons, and a positive correlation occurs among serotonergic neuron density, spine density of pyramidal cell dendrites, 5HT1AR-binding sites, and S100 expression (Ueda et al., 1995, 1996). The level of S100 also correlates with the degree of mental impairment in the patients (Kato et al., 1990). Moreover, a transgenic mouse developed to overexpress S100 possesses neuropathology and symptoms resembling Down’s syndrome (reviewed by Whitaker-Azmitia, 2001). Therefore, as with the other psychiatric disorders discussed, a component of the developmental pathology observed in Down’s syndrome can be attributed to dysfunctions of synaptic plasticity modulated by the serotonergic system.

VI. Conclusions

This review has considered the role of serotonin and serotonergic receptors in the neuroplastic events that create, repair, and degenerate the brain. Research spanning more than five decades has shown that serotonergic projections in the 150 SODHI AND SANDERS-BUSH brain have a widespread distribution and that these projections interact with other neurotransmitter systems, thereby influencing many, if not all, physiological functions. Evidence from biochemical, pharmacological, and clinical studies demonstrates the huge importance of an intact serotonergic system to support brain development and neurogenesis in the maintenance of normal CNS function. Serotonin acts as a growth factor and influences other growth factors during development. The high level of serotonin function during these crucial stages of brain development and the pharmacological evidence for impaired serotonergic function in several disparate brain disorders underpins the importance of under- standing this highly complex system. Increased insight may facilitate real progress in drug development, with the ultimate goal of preventing and even curing these debilitating illnesses.

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