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patogenesis

Since autism is considered primarily a brain disorder, much of the research over the
past decades has focused on the autistic brain. Different groups have reported a
wide range of anatomical abnormalities in autistic brains, such as reduced number
of Purkinje cells in the cerebellum [1-3]; an unusually rapid growth of the cerebral
cortical volume and head circumference during the first years after birth [4-9];
abnormal cortical minicolumns [10-13]; abnormalities of the limbic system [14-19];
abnormalities of the brainstem [20-22]; and other brain alterations [23-25].

It is unlikely that the autistic platelet hyperserotonemia is induced by the brain. The
human blood-brain barrier (BBB) becomes mature around one year after birth, if not
earlier [34,35], and is virtually impenetrable to 5-HT. Tryptophan, a 5-HT precursor,
can cross the BBB, but tryptophan levels do not appear to be altered in autistic
individuals [36]. Unlike the anatomy of the mature brain, platelet 5-HT levels should
be actively maintained, because the half-life of platelets is only a few days [37,38].
This suggests that the factor that causes the platelet hyperserotonemia continues
to be functionally active years after birth.

Increased synthesis of 5HT in the intestine (Croonenberghs et al. 2005), altered


release from the enterochromaffine cells (Janusonis 2005), increased uptake of
serotonin into platelets (Marazziti et al. 2000), diminished release from platelets
(Cook Jr and Leventhal 1996), or decreased peripheral 5HT catabolism (Anderson
1987) have been suggested as possible causes of the hyperserotonemia observed
in autistic subjects.

More than 99% of the whole blood serotonin is contained in platelets (Cook Jr and
Leventhal 1996). 5HT concentration in platelets, or the platelet serotonin level
(PSL), is regulated by several elements that control either the rate of the peripheral
5HT synthesis and metabolism (i.e., its concentration in blood plasma), or the rate
of its accumulation into- and release from the platelets. The platelet itself contains
three 5HT-associated proteins: 5HT transporter (5HTT), monoamine oxidase B
(MAOB) and 5HT2A receptor (5HT2Ar).
Mri in autism
When compared to neurotypicals, there is consistent evidence that individuals with
ASD have abnormalities in the serotonergic system including physiology,
neurobiology and genetics (Cook and Leventhal, 1996; Zafeiriou et al., 2009). For
example, research indicates that a significant proportion of subjects with ASD may
have hyperserotonaemia (Hranilovic et al., 2009). As well as detecting increased
blood levels of serotonin in first-degree relatives of subjects with ASD (Piven et al.,
1991; Leboyer et al., 1999), hyperserotonaemic parents of ASD subjects are
reported to have higher ratings of repetitive behaviours (Cook et al., 1994).
Additionally, the severity of repetitive behaviours in subjects with ASD are related to
the sensitivity of the serotonin-1d receptor, as measured by growth hormone
response to receptor agonist sumatriptan (Hollander et al., 2000)

Our results also add to existing evidence that serotonin may play a key role in the
pathophysiology of autism. The brain areas that we found to be differentially
modulated by ATD form part of a fronto-striato-thalamo-cerebellar network of
inhibitory control that develops progressively with age (Rubia et al., 2007), and has
intermediate-to-high levels of serotonin receptors and transporters (Pazos et al.,
1987; Varna s et al., 2004) in healthy populations.

Hence, it is unknown if the difference we found in brain function between autistic


individual and controls, and/or their differential modulation by tryptophan depletion,
are primary or secondary to differences in brain maturation or (most likely) a
complicated mixture of both. For example, in addition to its role as a
neurotransmitter, serotonin also acts as a trophic, or differentiation, factor in the
human brain (Whitaker-Azmitia, 2001). Given that ASD is a neurodevelopmental
disorder, the region-specific differences in brain activity we observed during
successful response inhibition (with and without ATD) may also be influenced by
disrupted trophic effects of serotonin.

Nejmoa

Recently, autism spectrum disorders have been linked to maternal use of SSRIs
during pregnancy.
In a casecontrol study involving 298 children with autism spectrum disorders, the
use of SSRIs by
the mother during pregnancy was shown to be associated with a risk of autism
spectrum disorder that was increased by a factor of 2. A causalcassociation is
plausible. Increased blood levels of the neurotransmitter serotonin have been
observed in persons with autism spectrum disorders.

Furthermore, this neurotransmitter appears to play an important role in early brain


development, and manipulation of serotonin homeostasis can alter neuroanatomical
and neurophysiological development and produce enduring behavioral changes.

Serotonin hipotesis
Serotonin, a neurotransmitter found throughout the brain and body, has long been
of interest in autism. Repeated findings of elevated platelet serotonin levels in
approximately one third of children with autism has led some to believe that
dysfunctional serotonin signaling may be a causal mechanism for the disorder.
Because serotonin is critical to fetal brain development, concerns have arisen
regarding prenatal exposure to substances that manipulate serotonin levels, such as
selective serotonin reuptake inhibitors (SSRIs). This review examines evidence
regarding the serotonin system and autism spectrum disorders (ASD), as well as
what the literature has reported thus far on developmental effects of prenatal
exposure to SSRIs. Possible mechanisms by which SSRIs could affect the fetus
during pregnancy and clinical implications are also discussed. Though the majority
of studies conducted in infants and children suggest prenatal exposure to SSRIs
does not affect neurodevelopment, interpretation must be tempered given small
sample sizes. The only published study that focused on prenatal SSRI exposure and
ASD found an increased risk with exposure to SSRIs, especially during the first
trimester. Obstacles that will be faced in future research are isolating medication
effects from maternal depression and, given the infrequent occurrence of exposure
and outcome, obtaining an adequate sample size. Whether serotonin is an etiologic
factor in ASD, and what it points to as a marker for subgrouping, remains unclear.
Understanding how the development of ASD might be affected by prenatal factors
that influence serotonin levels, such as SSRIs, could identify modifiable targets for
prevention.
Serotonin is a neurotransmitter found throughout the brain and body that has long
been of interest in autism. Repeated findings of an elevated platelet serotonin level
in approximately one third of children with autism [Anderson, Horne, Chatterjee, &
Cohen, 1990; Leboyer et al., 1999; McBride et al., 1998; Melke et al., 2008; Mulder
et al., 2004; Schain & Freedman, 1961] have led to the hypothesis that
dysfunctional serotonin signaling may be a causal mechanism for the disorder.
Given this theory and the importance of serotonin in fetal brain development,
concerns have arisen regarding exposure to selective serotonin reuptake inhibitors
(SSRIs) during pregnancy and possible adverse effects on long-term development,
in general, and the occurrence of autism, specifically [Hadjikhani, 2010; Oberlander,
Gingrich, & Ansorge, 2009].

Serotonin is derived from the essential amino acid tryptophan. Tryptophan cannot
be synthesized by humans; rather it must be supplied to the body by dietary intake,
such as from nuts, beans, beef, poultry, or eggs. Serotonin is synthesized both
centrally and peripherally and cannot cross the bloodbrain barrier (BBB). In the
brain, serotonergic cell bodies synthesize serotonin in the raph nuclei, located
along the midline of the brain stem. Neuronal projections from the raph nuclei
innervate most brain regions, distributing serotonin widely throughout the brain
[Berger, Gray, & Roth, 2009]. In the periphery, most serotonin is synthesized and
stored by enterochromaffin cells in the gut (an estimated 95% of serotonin in the
human body is found in the gut [Berger et al., 2009]) with a relatively small amount
absorbed into the bloodstream.
The majority of serotonin circulating in bloodmore than 99%is stored in platelets
via uptake by the serotonin transporter [Anderson et al., 1987]. Platelets are
derived from megakaryocytes where the serotonin transporter is transcribed and
translated [Giannaccini et al., 2010]. Serotonin is largely metabolized by
monoamine oxidase (MAO), of which there are two kinds, MAOA and MAOB. The
result of metabolism of serotonin is 5-hydroxyindoleacetic acid (5-HIAA). Serotonin
is also a precursor for melatonin, which is important for regulation of sleep and
wake cycles.

In neurons, serotonin is synthesized and stored in vesicles that release serotonin


into the synapse. Extracellular serotonin can then bind to postsynaptic receptors,
creating a cascade of events that ultimately leads to its multitudinous effects in the
body. Serotonin is cleared from the extracellular space by reuptake into the
presynaptic cell by the serotonin transporter where its action is terminated and it is
repackaged into vesicles or broken down by MAO. Serotonin autoreceptors located
on the presynaptic cell act as a feedback mechanism and facilitate the regulation of
serotonin synthesis and release.

Serotonins role in the body is pervasive, modulating many physiologic and


behavioral functions. In the central nervous system, serotonin is involved in the
regulation of mood, social behavior, aggression and impulsivity, appetite, pain
sensitivity, sleep, and learning. In the periphery, it affects muscletone and motor
output, vasoconstriction/ vasodilation, vomiting, peristalsis, clotting, cardiovascular
function, and immune signaling [Berger et al., 2009; Meredith, Chamba, Holder,
Barnes, & Gordon, 2005]. Serotoninexertsitsdiverseeffectsvianumerousserotonin
receptors [Pytliak, Vargova, Mechirova, & Felsoci, 2011] that are found in the central
and peripheral nervous system, as well as in various non-neuronal tissues such as
the gut, cardiovascular system, the blood, and the reproductive system, including
ovaries and the placenta.

Serotonin is one of the earliest monoamine neurotransmitters found in mammalian


species, and its neurons are among the first to be generated during brain
development. It is thought to act as a morphogen during embryonic development,
influencing the maturation of the brain [Cote et al., 2007; Ilkova et al., 2004]. At
that point in time, however, serotonin is not being synthesized by the embryo itself,
rather it is dependent on exogenous sources that are believed to be maternal in
origin [Cote et al., 2007]. A direct or indirect mechanism by which this embryo
maternal interaction might occur has not been identified. Recently, a study
demonstrated that the human placenta is able to synthesize serotonin from
maternal tryptophan [Bonnin et al., 2011
The embryo can synthesize serotonin independently from the mother by 5 weeks of
gestation when serotonergic neurons are evident in the human brain. After this
time, serotonin neurons rapidly increase through the 10th week of gestation. By the
15th week, serotonin cell bodies are in their typical organization in the raph nuclei
of the brain and by 4 months gestation, serotonin transporters and receptors are
present. Serotonin levels increase and remain high during infancy and early
childhood, declining to adult levels after the age of five