Dataset Information

Genetic Variation in Serotonin Transporter Modulates Tactile Hyperresponsiveness in ASD.

ABSTRACT: Several lines of evidence implicate dysfunction of the serotonin (5-HT) system in autism spectrum disorder (ASD). Specifically, the serotonin transporter (5-HTT, SERT) has been scrutinized as an ASD candidate risk gene. SERT plays key roles in the development of circuits that underlie sensory function, particularly in the somatosensory system. One previous study in ASD found association of a rare, hyperfunctional SERT variant with sensory aversion, but studies of common SERT variants have never examined sensory symptoms in ASD. Using standardized caregiver assessments of sensory function in children, we evaluated patterns of sensory responsiveness in 47 children with ASD and 38 typically developing (TD) children. Study participants were genotyped for the functional SERT promoter polymorphisms, 5-HTTLPR and rs25531, to test the hypothesis that the higher expressing genotypes would be associated with hyperresponsiveness to touch, a common sensory aversion in ASD. All measures of sensory hypo- and hyperresponsiveness were increased in children with ASD, with hyporesponsive sensory patterns negatively correlated to age and hyperresponsive sensory patterns positively correlated to repetitive behavior. Strikingly, high-expressing SERT genotypes were associated with increased tactile hyperresponsiveness in the ASD group. Our findings indicate genetic variation that increases SERT function may specifically impact somatosensory processing in ASD.

SUBMITTER: Schauder KB

PROVIDER: S-EPMC4281265 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Genetic Variation in Serotonin Transporter Modulates Tactile Hyperresponsiveness in ASD.

Schauder Kimberly B KB Muller Christopher L CL Veenstra-VanderWeele Jeremy J Cascio Carissa J CJ

Research in autism spectrum disorders 20150201

Several lines of evidence implicate dysfunction of the serotonin (5-HT) system in autism spectrum disorder (ASD). Specifically, the serotonin transporter (5-HTT, SERT) has been scrutinized as an ASD candidate risk gene. SERT plays key roles in the development of circuits that underlie sensory function, particularly in the somatosensory system. One previous study in ASD found association of a rare, hyperfunctional SERT variant with sensory aversion, but studies of common SERT variants have never ...[more]

PMID: 25558276

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Project description:BackgroundPreviously, 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.MethodsTo 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.ResultsOne 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.ConclusionsOur 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.

Project description:The serotonin transporter (SERT) gene, especially the short allele of the human serotonin transporter linked polymorphic region (5-HTTLPR), has been associated with the development of stress-related neuropsychiatric disorders. In line, exposure to early life stress in SERT knockout animals contributes to anxiety- and depression-like behavior. However, there is a lack of investigation of how early-life exposure to beneficial stimuli, such as tactile stimulation (TS), affects later life behavior in these animals. In this study, we investigated the effect of TS on social, anxiety, and anhedonic behavior in heterozygous SERT knockouts rats and wild-type controls and its impact on gene expression in the basolateral amygdala. Heterozygous SERT+/- rats were submitted to TS during postnatal days 8-14, for 10 min per day. In adulthood, rats were assessed for social and affective behavior. Besides, brain-derived neurotrophic factor (Bdnf) gene expression and its isoforms, components of glutamatergic and GABAergic systems as well as glucocorticoid-responsive genes were measured in the basolateral amygdala. We found that exposure to neonatal TS improved social and affective behavior in SERT+/- animals compared to naïve SERT+/- animals and was normalized to the level of naïve SERT+/+ animals. At the molecular level, we observed that TS per se affected Bdnf, the glucocorticoid-responsive genes Nr4a1, Gadd45β, the co-chaperone Fkbp5 as well as glutamatergic and GABAergic gene expression markers including the enzyme Gad67, the vesicular GABA transporter, and the vesicular glutamate transporter genes. Our results suggest that exposure of SERT+/- rats to neonatal TS can normalize their phenotype in adulthood and that TS per se alters the expression of plasticity and stress-related genes in the basolateral amygdala. These findings demonstrate the potential effect of a supportive stimulus in SERT rodents, which are more susceptible to develop psychiatric disorders.

Dataset Information

Genetic Variation in Serotonin Transporter Modulates Tactile Hyperresponsiveness in ASD.

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Genetic Variation in Serotonin Transporter Modulates Tactile Hyperresponsiveness in ASD.

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