Serotonin Theory of Autism

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Structure of the Monoamine Neurotransmitter Serotonin
(Retrieved on March 16, 2013)

Serotonin is a monoamine neurotransmitter that has long been implicated in the etiology of Autism. Serotonin was originally identified as playing a role in Autism in the 1960s when a study found that a significant number of Autistic individuals had increased levels of blood platelet serotonin [18]. Subsequent studies have found that changes in serotonin levels during development can affect white and grey matter density and overall brain morphology. Research also suggests that there may be an asymmetry in serotonin synthesis in the brain, which has been associated with deficiencies in language and communication (which are two of the core symptoms of Autism) [8]. A number of serotonin transporter gene polymorphisms have also been associated with Autism however, there is not a single gene variant responsible for Autism [11]. Most studies in past have implicated excess serotonin in the aberrant development in Autism in both the brain and the periphery. However, newer studies also suggest that serotonin depletion during development also produces a similar phenotype [11]. The role of serotonin in Autism still remains unclear possibly due to the heterogeneity of the disorder. The prevalence of Autism increases every year, so identifying the role of serotonin in Autism may help us understand the causes and potentially help us develop treatments for this complex disorder.

1.1 Role of Serotonin in Brain Development

Serotonin is a monoamine neurotransmitter thought to play an important role in brain development. It is thought to play a role in a number of processes including neurogenesis, synaptogenesis and dendritic maturation [10]. Changes in serotonin levels during development can have profound effects on these processes and on overall brain development [20].

1.1a Abnormalities in Serotonergic Axon Densities

Research suggests that Autistic individuals have abnormalities in serotonergic axon development. A study by Azmitia et al.[3] found increased density of serotonergic pathways in the forebrain of Autistic individuals across all ages. Postmortem studies that examined the densities of 5HT-immunoreactive axons found increase axonal densities throughout all the layers of the cortex and especially in layer one[3]. The increase in serotonergic tracts suggests that early on in development there may be an over-activation of the serotonergic system.

1.1b Effects of altered serotonin levels on serotonergic axon development

Serotonin is involved in a number of events during cortical development and abnormal levels of serotonin can lead to abnormalities in the organization of cortical neurons [10]. Studies using rodent models of ASD suggest that a serotonin deficiency during development can lead to a decrease in neuron numbers [4]. The symptoms displayed by mice with depleted serotonin resemble those of autistic individuals further suggesting that serotonin depletion may be involved [11]. However studies have also suggested that unusually high levels of serotonin can prevent normal spine development [17]. The conflicting evidence suggests there may be a fine balance of serotonin levels required for normal development.

1.2 Abnormalities in Serotonin Synthesis in Autism

Figure 2. Serotonin Synthesis
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Brain areas in red indicate areas with decreased
levels of serotonin synthesis.
Image extracted from study by Chandana et al (2005) [8]
(Retrieved on March 21, 2013)

There are a number of theories, which suggest that autistic individuals have abnormal serotonin levels during development. However it is not clear whether it is due to hyper-synthesis or hypo-synthesis of serotonin or if this varies across periods of development. A positron emission tomography (PET) study by Chugani et al. [7] found an asymmetry in the synthesis on serotonin in the brain of Autistic individuals. They found lower synthesis of 5HT in frontal cortex and the thalamus and increased synthesis in cerebellum and dentatothalamocortical pathway.
It has also been suggested that levels of 5HT synthesis change across development. A study by Chandana et al. [8] found decreased serotonin synthesis in the frontal cortex and continued back into the temporal lobe. They also tracked the changes across ages and the results suggest there is a critical period during which there are high levels of serotonin synthesis important for development. After the critical period of development, serotonin levels decrease with age. Results suggest that the levels of serotonin synthesis are abnormal during development [7] [8]. Figure 2 from the Chandana (2005)[8] paper shows areas in the brain with particularly low levels of serotonin synthesis. The areas identified in red in images B through D show the areas of the brain with decreased serotonergic synthesis as seen in a PET scan using an AMT tracer of serotonin synthesis.

1.3 Abnormalities in Serotonin transporters and receptors

Research has shown that there is a decreased level of serotonin binding in the brains of Autistic individuals. There is no clear explanation for why this is, but it may be due to abnormalities in serotonin receptors or transporters.
Changes in serotonin levels through parasite infection has also been shown to cause changes in behaviors.

1.3a Reduction in Serotonin transporter binding in specific brain regions

Figure 3. Serotonin Transporter Binding
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The above PET images demonstrate the significant decrease in serotonin binding capacity
in autistic individuals as compared to controls.
Image extracted from study by Nakamura et al (2010) [16]
Retrieved on March 21, 2013

A study by Makkonen et al. (2008)[14] used PET to examine the binding capacity of serotonin receptor transporter (SERT) in different regions of the brain. They found that SERT had decreased binding capacity in the medial frontal cortex of Autistic individuals. The medial frontal cortex has been implicated in a number of “theory of mind” processes that are deficient in Autistic individuals. A subsequent study by Nakamura et al. (2010)[16] found a global decrease in the serotonin binding capacity across the brain of Autistic individuals. The decrease in serotonin binding capacity was particularly profound in the striatum and orbitofrontal regions.

1.3b Serotonin Transporter gene polymorphisms

The SLC64A gene is found on chromosome 17q11-12 and encodes one of the serotonin transporter genes. The 5-hydroxytryptamine-transporter length polymorphism (5HTTLPR) of the SLC64A gene is thought to play a role in the abnormalities seen in serotonin transporter binding in Autism. However the results seem to differ greatly across countries. A study conducted in South Africa found that individuals with the short/short genotype had a higher incidence of Autism [2]. Conversely, a study conducted in Israel found a high association between the long/long genotype and Autism [21]. Furthermore a study by Ma et al. (2010)[13] found no difference in polymorphisms of the SLC64A gene in Autistic individuals. The mixed results of studies make it difficult to identify a specific genotype that is implicated in the abnormalities in serotonin transporter binding.
See: Genetics of Autism

1.4. Role of Serotonin in the Periphery

1.4a Blood Serotonin Differences in Autistic Individuals

Autism has long been associated with abnormally high levels of blood serotonin [18]. Serotonin receptors are not found exclusively in the brain, but also have targets on blood platelets. Also, it has been shown that the structure of serotonin molecules and serotonin transporter proteins (SERT) in the CNS and in the blood are identical. There are two major theories regarding the high levels of blood serotonin. Hyperserotonemia could be caused by a decreased ability of the platelets to bind serotonin or due to overall increased levels of serotonin in the body [1]. A study by Anderson et al. (2011)[1] did not find high levels of platelet poor plasma (PPP) serotonin binding levels in Autistic individuals when compared to controls. These findings suggest that hyperserotonemia is not due to a high level of serotonin exposure but rather an abnormality in the ability of platelets to handle serotonin.

1.4b Serotonin Receptors in Gastrointestinal System

Serotonin receptors have also been found in the mucous lining of the intestines [12]. This can have major implications since drugs that alter serotonin levels are taken orally. A study by Kazek et al. (2010)[12] found that Autistic individuals who had higher levels of blood platelet serotonin also had more severe gastrointestinal issues. It has also been suggested that hyperserotonemia may be caused by increased production of serotonin in the intestines [9]. There has not been a lot of research regarding the role of serotonin in the periphery, but it appears to be a promising area for subsequent research. See: how serotonin levels impact the sleep cycle
Also see other studies about how cells in the gut are related to Autism.

1.5 Effects of Pharmaceutically Altering Serotonin Levels

Mechanisms of SSRIs
Video explaining how SSRIs like Prozac work to increase serotonin levels

1.5a Effects of Increasing Serotonin Levels

In the past SSRIs have commonly been used to treat autistic symptoms however the efficacy of SSRI treatments remains unclear. A number of double-blind placebo-control studies examining the efficacy of SSRIs suggest they are effective in reducing repetitive behaviors associated with Autism [5] [15]. However, a meta-analysis conducted by Carrasco et al. (2012) [6] did not find a significant effect of SSRIs in reducing symptoms when controlling for publication biases. The efficacy of SSRI use in autism remains predominantly unclear and further studies are needed. See: Other treatments for Autism
Also see how SSRIs have been used to treat a number of disorders including eating disorders!

1.5b Effects of Prenatal SSRI Exposure

A recent study by Simpson et al. (2011)[19] tested the effects of pre-natal exposure to SSRIs on the cortical development of rodents. They found that exposure to SSRIs during development effects the organization of cortical neurons and leads to abnormal social behavior in rodents. These results are significant because they suggest that pre-natal exposure to SSRIs may lead to an increased risk of developing Autism. Investigation of pre-natal exposure to SSRIs in humans may give us insight into the role of SSRIs as teratogens.

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