Comprehensive Analysis of the 16p11.2 Deletion and Null Cntnap2 Mouse Models of Autism Spectrum Disorder

Abstract

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.

Germline Chd8 haploinsufficiency alters brain development in mouse

“…13 tested only male mice with a broad age range of 12–50 weeks of age, while our battery was conducted using both sexes at younger ages, between 6–16 weeks, to avoid aging as a confounding variable. We also note that several studies of other mouse models with mutations in genes implicated in ASD have not identified deficits in social behaviors 33 , potentially due to evolutionary divergence between mouse and human neurobiology, allele or genetic background differences, or sensitivity of methods used to evaluate ASD-relevant behavior in mice.…”

Targeted Interneuron Depletion in the Dorsal Striatum Produces Autism-like Behavioral Abnormalities in Male but Not Female Mice

“…ASD has a 5:1 male predominance (11); partially for this reason, most behavioral studies in mouse models have examined only male animals (28, 59, 62). The ability of an identical cellular depletion to produce such divergent effects in male and female mice draws attention to the importance of examining pathophysiological processes in both sexes.…”

Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder

“…Animals in cohort 2 were weaned at 4 weeks of age to match the conditions of the previous study, where later weaning was preferred due to small body size of the animals (Brunner et al . ). Breeding success and pup survival was similar among the four groups.…”

“…We provide back‐to‐back characterization of five different models of ASD through our previous companion paper on the first two models, Cntnap2 and 16p11 deletion (Brunner et al . ) and present here the results pertaining to the third, fourth and fifth models, namely two distinct Shank3 knockout (KO) models and the Cacna1c heterozygous (HET) model. We chose these models because of their strong construct validity based on human genetic evidence and because of their widespread use in the scientific community due to their availability through The Jackson's Laboratories as part of the Simons Foundation Autism Repository.…”