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.
[Show abstract] [Hide abstract] ABSTRACT: Background: Platelets have been proven to be a useful cellular model to study some neuropathologies, due to the overlapping biological features between neurons and platelets as granule secreting cells. Altered platelet dense granule morphology was previously reported in three autism spectrum disorder (ASD) patients with chromosomal translocations that disrupted ASD candidate genes NBEA, SCAMP5, and AMYSIN, but a systematic analysis of platelet function in ASD is lacking in contrast to numerous reports of elevated serotonin levels in platelets and blood as potential biomarker for ASD. Methods: We explored platelet count, size, epinephrine-induced activation, and dense granule ATP secretion in a cohort of 159 ASD patients, their 289 first-degree relatives (103 unaffected siblings, 99 mothers, and 87 fathers), 45 adult controls, and 65 pediatric controls. For each of the responses separately, a linear mixed model with gender as a covariate was used to compare the level between groups. We next investigated the correlation between platelet function outcomes and severity of impairments in social behavior (social responsiveness score (SRS)). Results: The average platelet count was increased in ASD patients and siblings vs. controls (ASD 320.3 × 10(9)/L, p = 0.003; siblings 332.0 × 10(9)/L, p < 0.001; controls 283.0 × 10(9)/L). The maximal platelet secretion-dependent aggregation response to epinephrine was not significantly lower for ASD patients. However, secondary wave responses following stimulation with epinephrine were more frequently delayed or absent compared to controls (ASD 52 %, siblings 45 %, parents 53 %, controls 22 %, p = 0.002). In addition, stimulated release of ATP from dense granules was reduced in ASD patients, siblings, and parents vs. controls following activation of platelets with either collagen (ASD 1.54 μM, p = 0.001; siblings 1.51 μM, p < 0.001; parents 1.67 μM, p = 0.021; controls 2.03 μM) or ADP (ASD 0.96 μM, p = 0.003; siblings 1.00 μM, p = 0.012; parents 1.17 μM, p = 0.21; controls 1.40 μM). Plasma serotonin levels were increased for ASD patients (n = 20, p = 0.005) and siblings (n = 20, p = 0.0001) vs. controls (n = 16). No significant correlations were found in the different groups between SRS scores and count, size, epinephrine aggregation, or ATP release. Conclusions: We report increased platelet counts, decreased platelet ATP dense granule secretion, and increased serotonin plasma levels not only in ASD patients but also in their first-degree relatives. This suggests that potential genetic factors associated with platelet counts and granule secretion can be associated with, but are not fully penetrant for ASD.0Comments 1Citation
- "This study also pointed out that the difference in serotonin is due only to the serotonin of the platelet fraction as the association was not found for serotonin levels in platelet-poor plasma. A study by Piven J et al. showed that serotonin levels in platelet-rich plasma of ASD patients with affected siblings were significantly higher than probands without affected siblings, though, the latter cases still had serotonin levels significantly higher than controls . A recent meta-analysis of all literature studies reporting ASD and control blood serotonin values concluded that elevated serotonin levels were recorded in 28.3 % in whole blood and 22.5 % in platelet-rich plasma samples of ASD patients, as reported in 15 and 4 studies, respectively, using different detection techniques . "
- "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). "
[Show abstract] [Hide abstract] 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.0Comments 11Citations
- "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). "