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Network modeling of the social, communication and restrictive/repetitive behaviors (RRBs) included in the definition of Autism Spectrum Disorder was performed. The Autism Diagnostic Interview-Revised (ADI-R) assessed behaviors in 139 pre-school cases at two cross-sections that averaged 34.8 months apart. Cross-sectional networks were based on the correlation matrix of the ADI-R behavioral items and the "bootCross" method was developed and enabled the estimation of a longitudinal network. At both stages, RRB items/nodes formed a consistent peripheral cluster, while social and communication nodes formed a core cluster that diverged with time. These differences in the nature and evolution of the RRB and socio-communicative dimensions indicate that their inter-behavior dynamics are very different. The most central behaviors across stages are proposed as prime targets for efficient therapeutic intervention.

To the Editor: The serotonin system is implicated in neurodevelopment. For example, maternal disruption of serotonin genes in rodents produces offspring neurodevelopmental changes (1). In humans, lower maternal whole blood [...]

Hyperserotonemia, or elevated levels of whole blood serotonin (WB5-HT), was the first biomarker linked to autism spectrum disorder (ASD). Despite numerous studies investigating the etiology of hyperserotonemia, results have been inconsistent. Recent findings suggest a relationship between the immune system and hyperserotonemia. The current study investigated whether intestinal 5-HT levels, 5-HT gene expression, or intestinal cell types predict WB5-HT. Participants included thirty-one males aged 3-18 who were classified into one of three groups: ASD and functional GI issues, typically developing with GI issues, and typically developing without GI issues. Samples from a lower endoscopy were analyzed to examine the pathways in predicting WB-5HT. Results demonstrated an association between T-Lymphocytes and WB5-HT.

Depression-, anxiety-, OCD- and autism-related behaviors were assessed in 118 high-functioning individuals with autism spectrum disorders (ASD) and in 2016 controls. The ASD group had a higher rate of clinical depression and markedly higher "insomnia" and "restlessness" scores. Network analysis and hierarchical cluster analysis in the ASD group revealed that depression and anxiety items clustered together, but separately from autism-related items. Compared to controls, "insomnia" and "restlessness" items in the ASD network of depression items were much more central (higher closeness, and betweenness centrality). Combined networks of depression-, anxiety-, and OCD-related items revealed that the control group depression item module was not preserved in ASD. The results indicate that depression is atypical in autism and suggest specific intervention targets.

The anxiety and autism realms are each complicated and heterogeneous, and relationships between the two areas are especially complex. Network analysis offers a promising approach to the phenotypic complexities of typical and atypical human behavior. The Revised Children's Anxiety and Depression Scale (RCADS) was used to assess anxiety in 126 high-functioning 9-13 year-olds with ASDs. Network graphs of Autism Diagnostic Observation Schedule items and RCADS anxiety total score, social, generalized, panic and separation anxiety subscores consistently found the anxiety node (score) to be highly peripheral. Also, the networks of RCADS anxiety items themselves were similar for the ASDs group and a general population comparison group (n = 2017). The results suggest anxiety is not a central part of autism and that anxiety is dynamically similar (aspects of anxiety relate to one another in a similar manner) in high-functioning autism and the general population.

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

We believe there are serious problems with a recently published and highly publicized paper entitled "Serotonin reduction in post-acute sequelae of viral infection." The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups. We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the "Discussion" section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, "Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment", it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration. In fact, one would expect a marked decline in platelet serotonin due to SSRIs' effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19. [ABSTRACT FROM AUTHOR]

Abstract Background Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes. Methods To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity. Results One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior. Conclusions Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.

A network conceptualization might contribute to understanding the occurrence and interacting nature of behavioral traits in the autism realm. Networks were constructed based on correlations of item scores of the Autism Diagnostic Observation Schedule for Modules 1, 2 and 3 obtained for a group of 477 Dutch individuals with developmental disorders. After combining Modules, networks were obtained and compared for male versus female, high- versus low-functioning, seizure versus non-seizure, autism spectrum disorder versus intellectual disability, and younger versus older subjects. The network visualizations and calculated network parameters provide new perspectives that generate new hypothesis and suggest follow-up studies. The approach should be useful in characterizing individuals and groups, in elucidating mechanisms of trait generation and routes to outcome phenotypes, and in suggesting points of intervention.

Network perspectives, in their emphasis on components and their interactions, might afford the best approach to the complexities of the ASD realm. Categorical approaches are unlikely to be fruitful as one should not expect to find a single or even predominant underlying cause of autism behavior across individuals. It is possible that the complex, highly interactive, heterogeneous and individualistic nature of the autism realm is intractable in terms of identifying clinically useful biomarker tests. It is hopeful from an emergenic perspective that small corrective changes in a single component of a deleterious network/configuration might have large beneficial consequences on developmental trajectories and in later treatment. It is suggested that the relationship between ASD and intellectual disability might be fundamentally different in single-gene versus nonsyndromic ASD. It is strongly stated that available biomarker "tests" for autism/ASD will do more harm than good. Finally, the serotonin-melatonin-oxidative stress-placental intersection might be an especially fruitful area of biological investigation.

Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-H[T.sub.4] agonist to Ala56 mice during development prevented Ala56associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-H[T.sub.4]-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation., Introduction The increasingly frequent diagnosis of autism spectrum disorder (ASD) is based on deficits in social communication and interaction together with restricted, repetitive patterns of behavior (1). Although the core [...]

Elevated whole blood serotonin levels are observed in more than 25 % of children with autism spectrum disorder (ASD). Co-occurring gastrointestinal (GI) symptoms are also common in ASD but have not previously been examined in relationship with hyperserotonemia, despite the synthesis of serotonin in the gut. In 82 children and adolescents with ASD, we observed a correlation between a quantitative measure of lower GI symptoms and whole blood serotonin levels. No significant association was seen between functional constipation diagnosis and serotonin levels in the hyperserotonemia range, suggesting that this correlation is not driven by a single subgroup. More specific assessment of gut function, including the microbiome, will be necessary to evaluate the contribution of gut physiology to serotonin levels in ASD., Author(s): Sarah Marler[sup.1] , Bradley J. Ferguson[sup.2] , Evon Batey Lee[sup.3] , Brittany Peters[sup.1] , Kent C. Williams[sup.4] , Erin McDonnell[sup.5] , Eric A. Macklin[sup.5] , Pat Levitt[sup.6] [sup.7] , [...]

Possible explanations for the well-replicated platelet hyperserotonemia of autism include an alteration in the platelet's handling of serotonin (5-hydroxyserotonin, 5-HT) or an increased exposure of the platelet to 5-HT. Measurement of platelet-poor plasma (PPP) levels of 5-HT appears to provide the best available index of in vivo exposure of the platelet to 5-HT. Mean (plus or minus SD) concentrations of PPP 5-HT observed in the autism (N = 18), hyperserotonemic subgroup (N = 5) and control (N = 24) groups were 0.86 plus or minus 0.53, 0.87 plus or minus 0.43 and 0.86 plus or minus 0.36 nM, respectively. The results suggest that the hyperserotonemia of autism is not due to increased exposure of the platelet to 5-HT and make it more likely that the factor(s) contributing to the hyperserotonemia of autism have to do with the platelet's handling of 5-HT.

The establishment of a criterion for operationally defining emergent phenomena in autism is needed. Key initial questions for autism researchers include how to define emergent phenomena in order to better diagnosis the condition.

Parents (N = 19) of children with autism spectrum disorders (ASD) and adult controls (N = 17) underwent positron emission tomography (PET) using [[superscript 18]F]setoperone to image cortical serotonin type-2 (5-HT2) receptors. The 5-HT2 binding potentials (BPs) were calculated by ratioing [[superscript 18]F]setoperone intensity in regions of interest (ROI) to cerebellar intensity. Cortical 5-HT2 BPs were significantly lower in parents compared to controls and platelet 5-HT levels were significantly negatively correlated with cortical 5-HT2 BP in parents. Lower cortical 5-HT2 receptor density in parents of children with ASD is consistent with reports of diminished 5-HT2 expression and functioning in individuals with ASD. Further research should examine the relationship of reduced 5-HT2 receptor expression to underlying causation and to clinical and neurochemical correlates of autistic behavior.

Associations between obstetric and parental psychiatric variables and subjects' Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) domain scores were examined using linear mixed effects models. Data for the 228 families studied were provided by the Autism Genetic Resource Exchange. Hypertension (P = 0.002), preeclampsia (P = 0.021) and generalized edema (P = 0.011) were associated with higher ADI-R communication scores. Hypertension (P = 0.011), albuminuria (P = 0.039) and generalized edema (P = 0.009) were associated with higher ADI-R repetitive behaviors scores. Parent depression was associated with higher ADI-R repetitive behaviors scores (P = 0.005), and parent anxiety with lower ADOS social/communication composite scores (P = 0.025). The associations between hypertension-related obstetric conditions and autistic severity warrant further investigation and raise intriguing questions regarding potential causal and modifying factors in autism.

The microbial metabolite indolepropionic acid (IPA) and related indolic metabolites, including indolecarboxylic acid (ICA), indolelactic acid (ILA), indoleacetic acid (IAA), indolebutyric acid (IBA), indoxylsulfate (ISO4), and indole, were determined in human plasma, plasma ultrafiltrate (UF), and saliva. The compounds were separated on a 150 × 3 mm column of 3 μm Hypersil C18 eluted with a mobile phase of 80% pH 5 0.01 M sodium acetate containing 1.0 g/L of tert-butylammonium chloride/20% acetonitrile and then detected fluorometrically. Levels of IPA in human plasma UF and of ILA in saliva are reported for the first time. The determination of IPA in plasma UF enables the first report of free plasma IPA, the presumed physiologically active pool of this important microbial metabolite of tryptophan. Plasma and salivary ICA and IBA were not detected, consistent with the absence of any prior reported values. Observed levels or limits of detection for other indolic metabolites usefully supplement limited prior reports. [ABSTRACT FROM AUTHOR]