Dataset Information

Sex-Dependent Motor Deficit and Increased Anxiety-Like States in Mice Lacking Autism-Associated Gene Slit3.

ABSTRACT: Altered neuronal connectivity has been implicated in the pathophysiology of Autism Spectrum Disorder (ASD). SLIT/ROBO signaling plays an important role in developmental processes of neuronal connectivity, including axon guidance, neuronal migration, and axonal and dendritic branching. Genetic evidence supports that SLIT3, one of the genes encoding SLITs, is associated with ASD. Yet the causal link between SLIT3 mutation and autism symptoms has not been examined. Here we assessed ASD-associated behaviors in Slit3 knockout (KO) mice. Our data showed that Slit3-KO mice exhibited reduced marble burying behaviors but normal social behaviors. In addition, Slit3-KO mice displayed hypolocomotion in the open field test and impaired motor coordination in the rotarod test. Anxiety-like behaviors were mainly observed in female KO mice assessed by three types of behavioral tests, namely, the open field test, elevated plus maze test, and light/dark box test. No differences were observed between KO and wildtype mice in recognition memory in the novel object recognition test or depression-like behavior in the tail suspension test. Taken together, loss of Slit3 may result in disrupted neural circuits related to motor function and increased anxiety-like states, which are co-occurring symptoms in ASD.

SUBMITTER: Park SM

PROVIDER: S-EPMC6243047 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Sex-Dependent Motor Deficit and Increased Anxiety-Like States in Mice Lacking Autism-Associated Gene Slit3.

Park Su Mi SM Plachez Céline C Huang Shiyong S

Frontiers in behavioral neuroscience 20181113

Altered neuronal connectivity has been implicated in the pathophysiology of Autism Spectrum Disorder (ASD). SLIT/ROBO signaling plays an important role in developmental processes of neuronal connectivity, including axon guidance, neuronal migration, and axonal and dendritic branching. Genetic evidence supports that SLIT3, one of the genes encoding SLITs, is associated with ASD. Yet the causal link between SLIT3 mutation and autism symptoms has not been examined. Here we assessed AS ...[more]

PMID: 30483073

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Project description:BackgroundChildren with autism spectrum disorder (ASD) often have co-occurring symptoms of attention-deficit/hyperactivity disorder (ADHD) and/or anxiety. It is unclear whether these disorders arise from shared or distinct developmental pathways. We explored this question by testing the specificity of early-life (infant and toddler) predictors of mid-childhood ADHD and anxiety symptoms compared to ASD symptoms.MethodsInfants (n = 104) at high and low familial risk for ASD took part in research assessments at 7, 14, 24 and 38 months, and 7 years of age. Symptoms of ASD, ADHD and anxiety were measured by parent report at age 7. Activity levels and inhibitory control, also measured by parent report, in infancy and toddlerhood were used as early-life predictors of ADHD symptoms. Fearfulness and shyness measured in infancy and toddlerhood were used as early-life predictors of anxiety symptoms. Correlations and path analysis models tested associations between early-life predictors and mid-childhood ADHD and anxiety symptoms compared to mid-childhood ASD symptoms, and the influence of controlling for ASD symptoms on those associations.ResultsIncreased activity levels and poor inhibitory control were correlated with ADHD symptoms and not ASD or anxiety; these associations were unchanged in path models controlling for risk-group and ASD symptoms. Increased fearfulness and shyness were correlated with anxiety symptoms, but also ASD symptoms. When controlling for risk-group in path analysis, the association between shyness and anxiety became nonsignificant, and when further controlling for ASD symptoms the association between fearfulness and anxiety became marginal.ConclusionsThe specificity of early-life predictors to ADHD symptoms suggests early developmental pathways to ADHD might be distinct from ASD. The overlap in early-life predictors of anxiety and ASD suggests that these disorders are difficult to differentiate early in life, which could reflect the presence of common developmental pathways or convergence in early behavioural manifestations of these disorders.

Project description:Background: Social-communication difficulties, a hallmark of ASD, autism spectrum disorder (ASD) are often observed in attention - deficit/ hyperactivity disorder (ADHD), although are not part of its diagnostic criteria. Despite sex differences in the prevalence of ASD and ADHD, research examining how sex differences manifest in social and communication functions in these disorders remains limited, and findings are mixed. This study investigated potential sex differences with age in social adaptive function across these disorders, relative to controls. Method: One hundred fifteen youth with ASD, 172 youth with ADHD, and 63 typically developing controls (age range 7-13 years, 75% males) were recruited from the Province of Ontario Neurodevelopmental Disorder (POND) Network. Social adaptive function was assessed using the Adaptive Behavior Assessment System-Second Edition (ABAS-II). The proportions of adaptive behaviors present in each skill area were analyzed as a binomial outcome using logistic regression, controlling for age, and testing for an age-by-sex interaction. In an exploratory analysis, we examined the impact of controlling for core symptom severity on the sex effect. Results: Significant sex-by-age interactions were seen within ASD in the communication (p = 0.005), leisure (p = 0.003), and social skill areas (p < 0.0001). In all three areas, lower scores (indicating poorer function) were found in females compared to males at older ages despite females performing better at younger ages. There were significant differences in the sex-by-age interactions in the social and leisure domains between those with ASD and typically developing controls, with typically developing females showing better scores at older, compared to younger, ages. There were also significant differences in the sex-by-age interactions between ASD and ADHD on the social and leisure domains, as females with ADHD consistently scored higher on social skills than males across all ages, unlike those with ASD. Sex differences across age in the social domains for ADHD were similar to those in the typically developing group. Conclusion: Sex differences in social and communication skill areas were observed between ASD and ADHD, and typically developing controls, with females with ASD performing worse than males at older ages, despite an earlier advantage. These findings reinforce the need to take a developmental approach to understanding sex differences which may have diagnostic, prognostic, and treatment implications.

Dataset Information

Sex-Dependent Motor Deficit and Increased Anxiety-Like States in Mice Lacking Autism-Associated Gene Slit3.

Publications

Sex-Dependent Motor Deficit and Increased Anxiety-Like States in Mice Lacking Autism-Associated Gene <i>Slit3</i>.

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