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 bio- chemical, pharmacological, and clinical studies demonstrates the huge import- ance 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 neuro- trophic factor (BDNF), S100 , and other chemical messengers, in addition to its cross talk with the GABAergic, glutamatergic, and dopaminergic neurotrans- mitter systems. Disruption of these processes may contribute to CNS disorders that have been associated with impaired development. Furthermore, many psy- chiatric 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 as- sociated 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 plasti- city 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 sero- tonin receptor subtypes, which they called 5-HT-M and 5-HT-D, after their an- tagonists, 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 re- ceptor 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 discov- ery 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 abun- dant in the hippocampus (Kosofsky and Molliver, 1987). The