Platelet serotonin, a possible marker for familial autism
Serotonin (5HT) levels in platelet-rich plasma were measured in 5 autistic subjects who had siblings with either autism or pervasive developmental disorder (PDD), 23 autistic subjects without affected siblings, and 10 normal controls. The 5HT levels of autistic subjects with affected siblings were significantly higher than probands without affected siblings, and autistic subjects without affected siblings had 5HT levels significantly higher than controls. Differences in 5HT levels remained significant after adjustment for sex, age, and IQ. These results suggest that 5HT level in autistic subjects may be associated with genetic liability to autism.
Available from: PubMed Central
- "A large body of evidence has led to the serotonin hypothesis of autism, which points out a deficiency in the brain serotonin system as a causal mechanism in ASD (Whitaker-Azmitia, 2005; Harrington et al., 2013). Early experimental data (Schain and Freedman, 1961), later confirmed by many research groups (Anderson et al., 1990; Piven et al., 1991; McBride et al., 1998; Mulder et al., 2004), have documented an increase of serotonin levels in blood platelets (hyperserotonemia) in one third of autistic patients. Conversely, a decreased uptake of tryptophan (the precursor of 5-HT) and a reduced 5-HT synthesis were detected in the brain of autistic children by positron emission tomography (PET) using the radioligand tracer alpha-methyl-tryptophan (Chugani et al., 1997, 1999; Chandana et al., 2005). "
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ABSTRACT: Serotonin type 7 receptors (5-HT7) are expressed in several brain areas, regulate brain development, synaptic transmission and plasticity, and therefore are involved in various brain functions such as learning and memory. A number of studies suggest that 5-HT7 receptors could be potential pharmacotherapeutic target for cognitive disorders. Several abnormalities of serotonergic system have been described in patients with autism spectrum disorder (ASD), including abnormal activity of 5-HT transporter, altered blood and brain 5-HT levels, reduced 5-HT synthesis and altered expression of 5-HT receptors in the brain. A specific role for 5-HT7 receptors in ASD has not yet been demonstrated but some evidence implicates their possible involvement. We have recently shown that 5-HT7 receptor activation rescues hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome, a monogenic cause of autism. Several other studies have shown that 5-HT7 receptors modulate behavioral flexibility, exploratory behavior, mood disorders and epilepsy, which include core and co-morbid symptoms of ASD. These findings further suggest an involvement of 5-HT7 receptors in ASD. Here, we review the physiological roles of 5-HT7 receptors and their implications in Fragile X Syndrome and other ASD.
Available from: Eileen Daly
- "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). "
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ABSTRACT: It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.
Available from: Juzoh Umemori
- "Improved understanding of distinct molecular mechanisms linked to SSRI action in ASD could facilitate optimal pharmacological intervention of individuals with ASD. Dysregulated serotonergic signaling in autism is supported by platelet hyperserotonemia in some of ASD individuals (Piven et al., 1991). Furthermore, linkage studies have identified ASD candidate genes in serotonergic pathways, including the gene that encodes SERT (SLC6A4) (Devlin et al., 2005; Brune et al., 2006). "
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ABSTRACT: Fluoxetine is used as a therapeutic agent for autism spectrum disorder (ASD), including Fragile X syndrome (FXS). The treatment often associates with disruptive behaviors such as agitation and disinhibited behaviors in FXS. To identify mechanisms that increase the risk to poor treatment outcome, we investigated the behavioral and cellular effects of fluoxetine on adult Fmr1 knockout (KO) mice, a mouse model for FXS. We found that fluoxetine reduced anxiety-like behavior of both wild-type and Fmr1 KO mice seen as shortened latency to enter the center area in the open field test. In Fmr1 KO mice, fluoxetine normalized locomotor hyperactivity but abnormally increased exploratory activity. Reduced brain-derived neurotrophic factor (BDNF) and increased TrkB receptor expression levels in the hippocampus of Fmr1 KO mice associated with inappropriate coping responses under stressful condition and abolished antidepressant activity of fluoxetine. Fluoxetine response in the cell proliferation was also missing in the hippocampus of Fmr1 KO mice when compared with wild-type controls. The postnatal mRNA expression of serotonin transporter (SERT) was reduced in the thalamic nuclei of Fmr1 KO mice during the time of transient innervation of somatosensory neurons suggesting that developmental changes of SERT expression were involved in the differential cellular and behavioral responses to fluoxetine in wild-type and Fmr1 mice. The results indicate that changes of BDNF/TrkB signaling contribute to differential behavioral responses to fluoxetine among individuals with ASD.
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