|  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 (mg/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 5-HT–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 a syndrome of distinctive repetitive behaviors. Genetic data
have connected 5-HT–related genes to disorders defined by symptoms
in these areas of behavior (e.g., mood, social phobia, obsessive-compulsive,
and anxiety disorders).
Discussion
of “autism-relevant” behaviors raises central issues regarding
the nature of autism and its underlying genetic factors. Family and twin
studies clearly show that autistic behavior is largely genetically determined
and suggest a heterogeneous and polygenetic basis. Molecular genetic studies
suggest that in most individuals a large number (>10) of genetic variants
are contributing to the altered behavior. It also appears that the variants
involved are common polymorphisms. It is natural to suggest that different
groups of variants are involved in affecting different components of altered
behavior. It also seems likely that certain genes and their variants may
play a role across behavioral domains. Serotonin-related genes are good
candidates for exerting such epistatic (multiple interacting genes affecting
a particular behavior) and pleiotropic (a specific gene affecting more
than one behavior) effects.
It
is unclear whether the same variants confer risk to disordered behavior
across syndromes, whether the behaviors are continuous with normal behaviors,
and whether genetic and behavioral interactions across domains are critical
for the expression of full-blown autism.
Genes
encoding a number of the components involved in 5-HT neural transmission
(Fig. 1) have been
examined as possible contributors to the potentially relevant behaviors
and disorders mentioned. Research in autism has focused on the influence
of 5-HT transporter gene (HTT) variants on risk to autism. Although
taken together the studies do not convincingly support a role for HTT
variants in determining risk, one of the latter studies did observe an
(yet to be replicated) allelic association with severity of communication
and social interaction impairment. Reported effects of 5-HT–related
alleles on therapeutic response to serotonergic antidepressants and atypical
neuroleptics (in mood disorders and psychosis, respectively) also tend
to link 5-HT and autism.
Drug
treatment studies have demonstrated that agents affecting the 5-HT system
can be useful for improving symptoms in individuals with autism. Drugs
targeting the 5-HT transporter, including the 5-HT reuptake inhibitors
fluoxetine, fluvoxamine, and clomipramine, are now widely used in autism.
The reuptake inhibitors appear to affect most aspects of autistic behavior,
including social relatedness. Several studies have found poor response
rates in younger subjects, with activation an especially common adverse
effect of the reuptake inhibitors. Risperidone, another frequently used
medication, also acts predominantly through a serotonergic target as it
is a potent antagonist at the 5-HT2A receptor. Paralleling
the drug treatment studies are neuroendocrine and behavioral challenge
paradigms using serotonergic agents. These studies have found abnormal
responses to the 5-HT releaser fenfluramine, the 5-HT precursor 5-hydroxytryptophan,
and the 5-HT1B/D receptor agonist sumatriptan. Depletion of
the 5-HT precursor tryptophan was reported to result in a significant
worsening of autistic behaviors.
The
platelet hyperserotonemia of autism has been especially well studied and
is generally considered to be one of the more robust and well-replicated
findings in biological psychiatry. Most studies have reported group mean
elevations of 25% to 50% in platelet serotonin in persons with autism.
Group differences appear to be more marked before puberty. Racial differences
in mean platelet 5-HT levels may have confounded some of the prior studies.
It appears that the elevation is not related to intelligence, and other
behavioral correlates have not become apparent. The mechanism of the alteration
and its possible relationship to brain abnormalities remain unknown. The
platelet does not appear to be exposed to greater amounts of 5-HT, given
normal urinary excretion of 5-HT and 5-HIAA and normal levels of plasma
5-HT. Thus attention had focused on the platelet’s handling of 5-HT.
To date, no clear alteration in the platelet has been identified, although
there is some suggestion that uptake may be increased in some subjects
with increased platelet levels.
Although
continued advances in the genetics of autism are expected, the major revelation
of the past 10 years has been the daunting complexity of the genetics
of autism. While improved drug treatment is likely using more specific
agents and with the application of pharmacogenetics, inferences regarding
etiopathophysiology based on drug effects will be tenuous. Early screening
and the application of neuropsychology to the identification of quantitative
behavioral phenotypes (e.g., eye tracking studies) will offer new perspectives
for dissecting and understanding autism-related behavior.
At
present, the areas of neuroimaging and postmortem brain research seem
to offer the greatest potential for rapidly advancing the field. The recent
availability of postmortem brain tissue, made possible through the efforts
of Dr. Margaret Bauman and colleagues (The Autism Research Foundation)
and now others (The Autism Tissue Program) has opened a wide window of
opportunity. Neurochemical and cytological investigations of the autistic
brain should no longer lag behind those in other areas of neuropsychiatry.
The analysis of pre- and postsynaptic serotonergic measures across a range
of cortical and subcortical regions should be particularly informative.
A number of structural imaging studies, initial functional magnetic resonance
imaging (fMRI) studies, as well as the limited imaging research examining
central 5-HT functioning, suggest that continued work in this area will
prove fruitful. Reciprocal interchange between imaging, neuropsychological,
and postmortem research should be especially useful and illuminating.
Finally, work on the mechanism of the platelet hyperserotonemia may provide
critically important information regarding possible central 5-HT dysfunction;
the advantages of having identified a specific biochemical alteration
in a delineated cell type might be best exploited by applying gene array
or expression technology to this question.
The
autism phenotype is gradually becoming less mysterious and the problems
and research issues are becoming better defined. However, the complex
and enigmatic nature of autism-related behaviors and their underlying
determinants present an exciting and difficult challenge to neuroscience.
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