Dataset Information

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions.

ABSTRACT: There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment.

SUBMITTER: Mitchell EJ

PROVIDER: S-EPMC7378168 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions.

Mitchell Emma J EJ Thomson David M DM Openshaw Rebecca L RL Bristow Greg C GC Dawson Neil N Pratt Judith A JA Morris Brian J BJ

Scientific reports 20200723 1

There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The abi ...[more]

PMID: 32704009

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Project description:Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.

Dataset Information

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions.

Publications

Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions.

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