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A social encounter drives gene expression changes linked to neuronal function, brain development, and related disorders in mice expressing the serotonin transporter Ala56 variant.

ABSTRACT: Multiple lines of evidence implicate the serotonin (5-HT) system in social function, including biomarker findings in autism spectrum disorder. In mice, knock-in of a rare Gly56Ala substitution in the serotonin transporter (SERT) causes elevated whole blood 5-HT levels, increased 5-HT clearance in the brain, and altered social and repetitive behavior. To further examine the molecular impact of this variant on social response, SERT Ala56 mutant mice and wildtype littermate controls were exposed to a social or non-social stimulus. We examined the differential activation of the prefrontal cortex, lateral amygdala, and medial amygdala, to social stimuli through RNA sequencing. Differentially expressed genes were enriched in axonal guidance signaling pathways, networks related to nervous system development and function, neurological and psychiatric disorders, and behavior. These identified pathways and networks may shed light on the molecular cascades underlying the impact of altered SERT function on social behavior.

SUBMITTER: O'Reilly KC

PROVIDER: S-EPMC7440397 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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A social encounter drives gene expression changes linked to neuronal function, brain development, and related disorders in mice expressing the serotonin transporter Ala56 variant.

O'Reilly Kally C KC Anacker Allison M J AMJ Rogers Tiffany D TD Forsberg C Gunnar CG Wang Jing J Zhang Bing B Blakely Randy D RD Veenstra-VanderWeele Jeremy J

Neuroscience letters 20200511

Multiple lines of evidence implicate the serotonin (5-HT) system in social function, including biomarker findings in autism spectrum disorder. In mice, knock-in of a rare Gly56Ala substitution in the serotonin transporter (SERT) causes elevated whole blood 5-HT levels, increased 5-HT clearance in the brain, and altered social and repetitive behavior. To further examine the molecular impact of this variant on social response, SERT Ala56 mutant mice and wildtype littermate controls were exposed to ...[more]

PMID: 32437898

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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:Altered serotonin (5-HT) signaling is associated with multiple brain disorders, including major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and autism spectrum disorder (ASD). The presynaptic, high-affinity 5-HT transporter (SERT) tightly regulates 5-HT clearance after release from serotonergic neurons in the brain and enteric nervous systems, among other sites. Accumulating evidence suggests that SERT is dynamically regulated in distinct activity states as a result of environmental and intracellular stimuli, with regulation perturbed by disease-associated coding variants. Our lab identified a rare, hypermorphic SERT coding substitution, Gly56Ala, in subjects with ASD, finding that the Ala56 variant stabilizes a high-affinity outward-facing conformation (SERT∗) that leads to elevated 5-HT uptake in vitro and in vivo. Hyperactive SERT Ala56 appears to preclude further activity enhancements by p38α mitogen-activated protein kinase (MAPK) and can be normalized by pharmacological p38α MAPK inhibition, consistent with SERT Ala56 mimicking, constitutively, a high-activity conformation entered into transiently by p38α MAPK activation. We hypothesize that changes in SERT-interacting proteins (SIPs) support the shift of SERT into the SERT∗ state which may be captured by comparing the composition of SERT Ala56 protein complexes with those of wildtype (WT) SERT, defining specific interactions through comparisons of protein complexes recovered using preparations from SERT-/- (knockout; KO) mice. Using quantitative proteomic-based approaches, we identify a total of 459 SIPs, that demonstrate both SERT specificity and sensitivity to the Gly56Ala substitution, with a striking bias being a loss of SIP interactions with SERT Ala56 compared to WT SERT. Among this group are previously validated SIPs, such as flotillin-1 (FLOT1) and protein phosphatase 2A (PP2A), whose functions are believed to contribute to SERT microdomain localization and regulation. Interestingly, our studies nominate a number of novel SIPs implicated in ASD, including fragile X mental retardation 1 protein (FMR1) and SH3 and multiple ankyrin repeat domains protein 3 (SHANK3), of potential relevance to long-standing evidence of serotonergic contributions to ASD. Further investigation of these SIPs, and the broader networks they engage, may afford a greater understanding of ASD as well as other brain and peripheral disorders associated with perturbed 5-HT signaling.

Dataset Information

A social encounter drives gene expression changes linked to neuronal function, brain development, and related disorders in mice expressing the serotonin transporter Ala56 variant.

Publications

A social encounter drives gene expression changes linked to neuronal function, brain development, and related disorders in mice expressing the serotonin transporter Ala56 variant.

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