Comprehensive Behavioral Phenotyping of a 16p11.2 Del Mouse Model for Neurodevelopmental Disorders.

Abstract

The microdeletion of copy number variant 16p11.2 is one of the most common genetic mutations associated with neurodevelopmental disorders, such as Autism Spectrum Disorders (ASDs). Here, we describe our comprehensive behavioral phenotyping of the 16p11.2 deletion line developed by Alea Mills on a C57BL/6J and 129S1/SvImJ F1 background (Delm ). Male and female Delm mice were tested in developmental milestones as preweanlings (PND2-PND12), and were tested in open field activity, elevated zero maze, rotarod, novel object recognition, fear conditioning, social approach, and other measures during post-weaning (PND21), adolescence (PND42), and adulthood (>PND70). Developmentally, Delm mice show distinct weight reduction that persists into adulthood. Delm males also have reduced grasp reflexes and limb strength during development, but no other reflexive deficits whereas Delm females show limb strength deficits and decreased sensitivity to heat. In a modified version of a rotarod task that measures balance and coordinated motor activity, Delm males, but not females, show improved performance at high speeds. Delm males and females also show age-specific reductions in anxiety-like behavior compared with WTs, but neither sex show deficits in a social preference task. When assessing learning and memory, Delm males and females show age-specific impairments in a novel object or spatial object recognition, but no deficits in contextual fear memory. This work extends the understanding of the behavioral phenotypes seen with 16p11.2 deletion by emphasizing age and sex-specific deficits; important variables to consider when studying mouse models for neurodevelopmental disorders. LAY SUMMARY: Autism spectrum disorder is a common neurodevelopmental disorder that causes repetitive behavior and impairments in social interaction and communication. Here, we assess the effects of one of the most common genetic alterations in ASDs, a deletion of one copy of 29 genes, using a mouse model. These animals show differences in behavior between males and females and across ages compared with control animals, including changes in development, cognition, and motor coordination. Autism Res 2020, 13: 1670-1684. © 2020 International Society for Autism Research and Wiley Periodicals LLC.