Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time.
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ABSTRACT:
SUBMITTER: Lee DK
PROVIDER: S-EPMC8410666 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRecent progress in genomics has contributed to the identification of a large number of autism spectrum disorder (ASD) risk genes, many of which encode synaptic proteins. Our understanding of ASDs has advanced rapidly, partly owing to the development of numerous animal models. Extensive characterizations using a variety of behavioral batteries that analyze social behaviors have shown that a subset of engineered mice that model mutations in genes encoding Shanks, a family of excitatory postsynaptic scaffolding proteins, exhibit autism-like behaviors. Although these behavioral assays have been useful in identifying deficits in simple social behaviors, alterations in complex social behaviors remain largely untested.MethodsTwo syndromic ASD mouse models-Shank2 constitutive knockout [KO] mice and Shank3 constitutive KO mice-were examined for alterations in social dominance and social cooperative behaviors using tube tests and automated cooperation tests. Upon naïve and salient behavioral experience, expression levels of c-Fos were analyzed as a proxy for neural activity across diverse brain areas, including the medial prefrontal cortex (mPFC) and a number of subcortical structures.FindingsAs previously reported, Shank2 KO mice showed deficits in sociability, with intact social recognition memory, whereas Shank3 KO mice displayed no overt phenotypes. Strikingly, the two Shank KO mouse models exhibited diametrically opposed alterations in social dominance and cooperative behaviors. After a specific social behavioral experience, Shank mutant mice exhibited distinct changes in number of c-Fos+ neurons in the number of cortical and subcortical brain regions.ConclusionsOur results underscore the heterogeneity of social behavioral alterations in different ASD mouse models and highlight the utility of testing complex social behaviors in validating neurodevelopmental and neuropsychiatric disorder models. In addition, neural activities at distinct brain regions are likely collectively involved in eliciting complex social behaviors, which are differentially altered in ASD mouse models.
| S-EPMC7602353 | biostudies-literature
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.
| S-EPMC4113141 | biostudies-literature
Project description:Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan-McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.
| S-EPMC3090611 | biostudies-literature
Project description:Mutations and deletions in the SHANK3 gene cause the major neurodevelopmental features of Phelan-McDermid syndrome (PMS), which is characterized by intellectual disability, autism spectrum disorder, and sensory hyporeactivity. SHANK3 encodes a key structural component of excitatory synapses important for synaptogenesis. Clinical assessments and limited brain imaging studies of patients with PMS have uncovered regional volume reductions and white matter thinning. While these impairments have been replicated ex vivo in pups of a rat model, brain structure has not been assessed in rats in vivo or in adults. We assessed the brain structure of heterozygous and homozygous adult Shank3-deficient male rats in comparison to wild-type littermates with magnetic resonance imaging using both anatomical assessments and diffusion tensor imaging (DTI). Shank3-deficient rats showed a reduction in overall brain size and the absolute volume of the neocortex, piriform cortex, thalamus, forebrain, inferior and superior colliculi, internal capsule, and anterior commissure. The superior colliculus was decreased in relative volume. DTI revealed that axial diffusion and fractional anisotropy were reduced in the external capsule and mean diffusion was increased in the fornix, suggesting that restriction of diffusion perpendicular to the axis of the axonal fibers was impaired in these white matter tracts. Therefore, Shank3-deficient rats replicate the reduced brain volume and altered white matter phenotypes present in PMS. Our results indicate that the loss of a glutamatergic synaptic protein, Shank3, has structural consequences at the level of the whole brain. The brain regions that were altered represent potential cross-species structural biomarkers that warrant further study.
| S-EPMC9292834 | biostudies-literature
Project description:Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy.
| S-EPMC4948673 | biostudies-literature
Project description:Mouse models of autism can be used to study evolutionarily conserved mechanisms underlying behavioral abnormalities in social communication and repetitive behaviors. SHANK genes code for synaptic scaffolding proteins at excitatory synapses and mutations in all SHANK genes have been associated with autism. Here, we present three behavioral aspects of the mutant mice deleted for exon 16 in Shank2. First, we treated Shank2 mutant mice with methylphenidate to rescue the hyperactivity. Our failure to do so suggests that the hyperactivity displayed by Shank2 mutant mice is not related to the one displayed by the typical mouse models of hyperactivity, and might be more closely related to manic-like behaviors. Second, by testing the effect of group housing and social isolation on social interest, we highlighted that Shank2 mutant mice lack the typical flexibility to modulate social interest, in comparison with wild-type littermates. Finally, we established a new protocol to test for social recognition in a social context. We used this protocol to show that Shank2 mutant mice were able to discriminate familiar and unknown conspecifics in free interactions. Altogether, these studies shed some light on specific aspects of the behavioral defects displayed by the Shank2 mouse model. Such information could be used to orient therapeutic strategies and to design more specific tests to characterize the complex behavior of mouse models of autism.
| S-EPMC6180161 | biostudies-literature
Project description:A plethora of studies stress students' self-regulated learning (SRL) skills to be conditional for successful learning in school and beyond. In general, self-regulated learners are actively engaged in constructing their own understanding also including the regulation of contextual features in the environment. Within the contextual features, the regulation of peer interaction is necessary, because college courses increasingly require peer learning. This goes along with the increasing interest for online learning settings, due in no small part to the recent COVID-19 pandemic. In the present study we explore how social presence (i.e., the degree to which the other person is perceived as physical "real"), social space (i.e., trust building between peers) and sociability (i.e., the degree to which the virtual learning environment supports social presence and social space) are essential elements in the regulation of online peer interaction. To shed light in this matter, higher education students were qualitatively followed for 1 year in an online academic writing course by using retrospective interviews (n = 7) and reflective questions (n = 62). Additionally, for social presence, students' perceptions were quantitatively measured with a validated questionnaire (n = 41). The results show that the planning phase is the most important phase for supporting students' social presence because that is where the regulation of peer interaction becomes important. The sociability has an important role here as well becoming less prominent further on in the self-regulation process. In the SRL follow-up phases, students look for other ways to increase their social presence and social space in order to shape the regulation of peer interaction from a position of trust. In the evaluation phase, students are aware of the importance of social presence but less of social space for the regulation of peer interaction. We conclude with some design principles to facilitate students' regulation of peer interaction in online settings.
| S-EPMC9081834 | biostudies-literature
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.
| S-EPMC8474908 | biostudies-literature
Project description:To determine whether histone deacetylase (HDAC) inhibition has genome-wide effects on gene expression, we used RNA sequencing to analyze the mRNA profile in prefrontal cortex (PFC) of wild-type (WT) and Shank3-deficient (Shank3+/ΔC) mice treated with romidespin or saline control. We mapped the sequences to 24,420 mouse genes. Compared to WT, 365 genes in saline-treated Shank3+/ΔC mice showed a change in expression values of at least 1.2 fold and p ≤ 0.01 (213 downregulated, 152 upregulated). In romidepsin-treated Shank3+/ΔC mice, ~88% of the downregulated genes (n=187 genes) were normalized to control values. Further analysis of the romidepsin-restored genes revealed enrichment in actin cytoskeleton-mediated transport, signal transduction pathways, and developmental processes.
2018-03-12 | GSE109328 | GEO
Project description:The sense of controlling one's own actions is fundamental to normal human mental function, and also underlies concepts of social responsibility for action. However, it remains unclear how the wider social context of human action influences sense of agency. Using a simple experimental design, we investigated, for the first time, how observing the action of another person or a robot could potentially influence one's own sense of agency. We assessed how observing another's action might change the perceived temporal relationship between one's own voluntary actions and their outcomes, which has been proposed as an implicit measure of sense of agency. Working in pairs, participants chose between two action alternatives, one rewarded more frequently than the other, while watching a rotating clock hand. They judged, in separate blocks, either the time of their own action, or the time of a tone that followed the action. These were compared to baseline judgements of actions alone, or tones alone, to calculate the perceptual shift of action toward outcome and vice versa. Our design focused on how these two dependent variables, which jointly provide an implicit measure of sense of agency, might be influenced by observing another's action. In the observational group, each participant could see the other's actions. Multivariate analysis showed that the perceived time of action and tone shifted progressively toward the actual time of outcome with repeated experience of this social situation. No such progressive change occurred in other groups for whom a barrier hid participants' actions from each other. However, a similar effect was observed in the group that viewed movements of a human-like robotic hand, rather than actions of another person. This finding suggests that observing the actions of others increases the salience of the external outcomes of action and this effect is not unique to observing human agents. Social contexts in which we see others controlling external events may play an important role in mentally representing the impact of our own actions on the external world.
| S-EPMC5003881 | biostudies-literature