Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

Abstract

Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms, and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. We therefore characterized gait using the DigiGait assay in two different NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1+/R681X mouse, which models a patient-derived heterozygous germline NF1 mutation. We collected longitudinal data across five developmental time points (postnatal days 21-30) and one early adulthood time point. Compared to wild type littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across Nf1+/R681X mouse development persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in CD mice largely resolved by adulthood. These findings suggest that gait subcomponents affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models, and a platform to examining circuits or longitudinal therapeutics. Lay SummaryGait changes have been reported in Williams Syndrome and Neurofibromatosis Type 1, but how these changes develop over time has not been explored. We therefore studied gait in mouse models of these two disorders across time. We found multiple shared differences in gait as compared to healthy controls at the younger ages in both models. However, those differences were resolved in the Williams Syndrome model by adulthood, yet persisted in the Neurofibromatosis Type 1 model.