Genetics of childhood disorders: XLV. Autism, part 4: serotonin in autism.

Early experiments on the isolation and identification of serotonin (5-hydroxytryptamine, 5-HT) were carried out from the late 1930s through the early 1950s. These studies demonstrated the presence of 5-HT in blood and in enterochromaffin cells of the gut, and they established the indole structure of the molecule. In 1953, it was shown that the mammalian brain contained appreciable (μg/g) quantities of 5-HT. A consideration of 5-HT’s actions as a vasoconstrictor and cardiostimulant, the parallels between 5-HT and the then-nascent neurotransmitters norepinephrine and acetylcholine, and commonalities with the molecular structure of lysergic acid led rapidly to suggestions that 5-HT might play a role in mental disorders. In 1961, Shain and Freedman reported finding elevated levels of platelet 5-HT in individuals with autism. Serious consideration of the role of 5-HT in autism dates from this time. Although platelet hyperserotonemia has continued to provide an impetus for the study of 5-HT in autism, a wide range of neurobiological, pharmacological, and genetic data has contributed to the continuing interest in this area. As background, the central serotonergic system is depicted in Figure 1. As shown, nearly all cell bodies of central 5-HT neurons are located in the dorsal midbrain and brainstem and project in a pervasive fashion throughout the brain. 5-HT is produced from the dietary amino acid precursor, tryptophan, and metabolized predominantly to 5-hydroxyindoleacetic acid (5-HIAA). As might be expected from its phylogenetically ancient role in neural transmission and its extensive CNS projections, 5-HT has been shown to play a key role in a variety of behaviors and processes including sensory gating, behavioral inhibition, appetite, aggression, sleep, mood, affiliation, and neuroendocrine secretion. Theoretical considerations underlying the rationale for the study of 5-HT in autism include 5-HT’s role in neurodevelopment, its especially rich innervation of limbic areas critical for emotional expression and social behavior, and the involvement of 5-HT in a wide range of behaviors often observed to be affected in individuals with autism. Providing a more empirical basis are studies showing therapeutic benefit of serotonergic agents in autism, reports of 5-HT–related neuroendocrine abnormalities, the well-characterized platelet hyperserotonemia, and recently reported associations between autism and 5HT–related genes. The critical involvement of 5-HT in guiding neurodevelopment and the extended ontogeny of the central serotonergic system provide theoretical bases for positing a role for 5-HT in the etiology and pathophysiology of autism and related pervasive developmental disorders. Serotonin and its associated transporter and receptors are found very early in development (embryonic day 11–12 in the rat, by 4 months of gestation in humans). Much of the early expression of 5-HT appears to be related to its role as a growth factor and regulator of neuronal development. Thus, in addition to functioning as a modulator of neural transmission, 5-HT appears to have critical effects on neurogenesis, morphogenesis, and synaptogenesis in the developing brain. Serotonin genetics and neurodevelopment intersect in the recent observation of an effect of transporter gene variants (HTT intron 2 alleles) on patterns of 5-HT transporter gene expression in the developing mammalian brainstem. Accumulating evidence indicates that 5-HT projections continue to undergo age-related change through early adulthood and that the serotonergic system is particularly plastic. Consideration of the fundamental social deficit in autism and of the behavioral sequelae of amygdalar lesions, as well as the results of cytological analysis of postmortem brain tissue, have made the amygdala and associated areas of limbic cortex of particular interest. The core social relatedness deficits in autism focus research attention on the rostral limbic system, including the amygdala, septum, medial orbitofrontal cortex, anterior insular cortex, anterior cingulate cortex, accumbens, and hippocampus. The various limbic areas are richly enervated with serotonergic projections. The cerebellum has also received intensive study in autism, with cerebellar alterations suggested due to its role in attention regulation and motor control and to the results of postmortem (cytological) and imaging studies. Although 5-HT innervation of the cerebellum is less prominent, 5-HT projections are critical to cerebellar function. Early transient dense expression of 5-HT receptors (5-HT1A) appears important in the formation of the cerebellar cortex. In adult animals, 5-HT plays important roles mediating the diverse autism-relevant behaviors of sleep, mood, arousal, aggression, impulsivity, and affiliation. Reduced serotonergic function has been associated with worsened sleep, depressed mood, altered arousal, increased aggression, greater impulsivity, and reduced social behavior. Although 5-HT tends to play an inhibitory role in the CNS, its actions are complex and depend greatly upon the specific location and class of receptor stimulated. For instance, markedly increasing extracellular 5-HT release can reduce appetite and aggression but also can lead to