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Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time.

ABSTRACT: Despite a growing understanding of the molecular and developmental basis of autism spectrum disorder (ASD), how the neuronal encoding of social information is disrupted in ASD and whether it contributes to abnormal social behavior remains unclear. Here, we disrupted and then restored expression of the ASD-associated gene Shank3 in adult male mice while tracking the encoding dynamics of neurons in the medial prefrontal cortex (mPFC) over weeks. We find that Shank3 disruption led to a reduction of neurons encoding the experience of other mice and an increase in neurons encoding the animal's own experience. This shift was associated with a loss of ability by neurons to distinguish other from self and, therefore, the inability to encode social agency. Restoration of Shank3 expression in the mPFC reversed this encoding imbalance and increased sociability over 5-8 weeks. These findings reveal a neuronal-encoding process that is necessary for social behavior and that may be disrupted in ASD.

SUBMITTER: Lee DK

PROVIDER: S-EPMC8410666 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time.

Lee Daniel K DK Li S William SW Bounni Firas F Friedman Gabriel G Jamali Mohsen M Strahs Leah L Zeliger Omer O Gabrieli Pauline P Stankovich Michael A MA Demaree Jack J Williams Ziv M ZM

Nature neuroscience 20210712 9

Despite a growing understanding of the molecular and developmental basis of autism spectrum disorder (ASD), how the neuronal encoding of social information is disrupted in ASD and whether it contributes to abnormal social behavior remains unclear. Here, we disrupted and then restored expression of the ASD-associated gene Shank3 in adult male mice while tracking the encoding dynamics of neurons in the medial prefrontal cortex (mPFC) over weeks. We find that Shank3 disruption led to a reduction of ...[more]

PMID: 34253921

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Project description:BackgroundConsiderable clinical heterogeneity has been well documented amongst individuals with autism spectrum disorders (ASD). However, little is known about the biological mechanisms underlying phenotypic diversity. Genetic studies have established a strong causal relationship between ASD and molecular defects in the SHANK3 gene. Individuals with various defects of SHANK3 display considerable clinical heterogeneity. Different lines of Shank3 mutant mice with deletions of different portions of coding exons have been reported recently. Variable synaptic and behavioral phenotypes have been reported in these mice, which makes the interpretations for these data complicated without the full knowledge of the complexity of the Shank3 transcript structure.MethodsWe systematically examined alternative splicing and isoform-specific expression of Shank3 across different brain regions and developmental stages by regular RT-PCR, quantitative real time RT-PCR (q-PCR), and western blot. With these techniques, we also investigated the effects of neuronal activity and epigenetic modulation on alternative splicing and isoform-specific expression of Shank3. We explored the localization and influence on dendritic spine development of different Shank3 isoforms in cultured hippocampal neurons by cellular imaging.ResultsThe Shank3 gene displayed an extensive array of mRNA and protein isoforms resulting from the combination of multiple intragenic promoters and extensive alternative splicing of coding exons in the mouse brain. The isoform-specific expression and alternative splicing of Shank3 were brain-region/cell-type specific, developmentally regulated, activity-dependent, and involved epigenetic regulation. Different subcellular distribution and differential effects on dendritic spine morphology were observed for different Shank3 isoforms.ConclusionsOur results indicate a complex transcriptional regulation of Shank3 in mouse brains. Our analysis of select Shank3 isoforms in cultured neurons suggests that different Shank3 isoforms have distinct functions. Therefore, the different types of SHANK3 mutations found in patients with ASD and different exonic deletions of Shank3 in mutant mice are predicted to disrupt selective isoforms and result in distinct dysfunctions at the synapse with possible differential effects on behavior. Our comprehensive data on Shank3 transcriptional regulation thus provides an essential molecular framework to understand the phenotypic diversity in SHANK3 causing ASD and Shank3 mutant mice.

Project description:BackgroundRoad traffic air pollution is linked with an increased risk of autistic spectrum disorder (ASD). The aim of this study is to assess the effect of exposure to prenatal or postnatal traffic-related air pollution combining concomitant noise pollution on ASD-related epigenetic and behavioral alternations on offspring.MethodsA 2 × 2 factorial analysis experiment was designed. Wistar rats were exposed at different sites (L group: green space; H group: crossroads) and timings (E group: full gestation; P group: 21 days after birth) at the same time, and air pollutants of nitrogen dioxide (NO2) and fine particles (PM2.5) were meanwhile sampled. On postnatal day 25, brains from offspring of each group were extracted to determine the levels of DNA methylation in Shank3 (three parts: Shank3_01, Shank3_02, Shank3_03) and MeCP2 (two parts: MeCP2_01, MeCP2_02) promoter regions, H3K4me3 and H3K27me3 after three-chamber social test. Meanwhile, the Shank3 and MeCP2 levels were quantified.ResultsThe concentrations of PM2.5 (L: 58.33 µg/m3; H: 88.33 µg/m3, P < 0.05) and NO2 (L: 52.76 µg/m3; H: 146.03 µg/m3, P < 0.01) as well as the intensity of noise pollution (L: 44.4 dB (A); H: 70.1 dB (A), P < 0.001) differed significantly from 18:00 to 19:00 between experimental sites. Traffic pollution exposure (P = 0.006) and neonatal exposure (P = 0.001) led to lower weight of male pups on PND25. Male rats under early-life exposure had increased levels of Shank3 (Shank3_02: timing P < 0.001; site P < 0.05, Shank3_03: timing P < 0.001) and MeCP2 (MeCP2_01: timing P < 0.001, MeCP2_02: timing P < 0.001) methylation and H3K4me3 (EL: 11.94 µg/mg; EH: 11.98; PL: 17.14; PH: 14.78, timing P < 0.05), and reduced levels of H3K27me3 (EL: 71.07 µg/mg; EH: 44.76; PL: 29.15; PH: 28.67, timing P < 0.001; site P < 0.05) in brain compared to those under prenatal exposure. There was, for female pups, a same pattern of Shank3 (Shank3_02: timing P < 0.001; site P < 0.05, Shank3_03: timing P < 0.001) and MeCP2 (MeCP2_01: timing P < 0.05, MeCP2_02: timing P < 0.001) methylation and H3K4me3 (EL: 11.27 µg/mg; EH: 11.55; PL: 16.11; PH: 15.44, timing P < 0.001), but the levels of H3K27me3 exhibited an inverse trend concerning exposure timing. Hypermethylation at the MeCP2 and Shank3 promoter was correlated with the less content of MeCP2 (female: EL: 32.23 ng/mg; EH: 29.58; PL: 25.01; PH: 23.03, timing P < 0.001; site P < 0.05; male: EL: 31.05 ng/mg; EH: 32.75; PL: 23.40; PH: 25.91, timing P < 0.001) and Shank3 (female: EL: 5.10 ng/mg; EH: 5.31; PL: 4.63; PH: 4.82, timing P < 0.001; male: EL: 5.40 ng/mg; EH: 5.48; PL: 4.82; PH: 4.87, timing P < 0.001). Rats with traffic pollution exposure showed aberrant sociability preference and social novelty, while those without it behaved normally.ConclusionsOur findings suggest early life under environmental risks is a crucial window for epigenetic perturbations and then abnormalities in protein expression, and traffic pollution impairs behaviors either during pregnancy or after birth.

Dataset Information

Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time.

Publications

Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time.

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