Abstract
BackgroundMotor 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.MethodsWe characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1+/R681X mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21–30) and one early adulthood time point.ResultsCompared to wildtype 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 development in the Nf1+/R681X mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood.ConclusionsThese findings suggest that the subcomponents of gait 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.
Highlights
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)
We used a longitudinal design to quantify gait across development and in adulthood to parse resolution versus persistence of gait phenotypes in Nf1+/R681X and WS mouse models, as well as characterize a comprehensive set of spatial, temporal, and postural gait subcomponents and identify those most affected in these NDDs
The perturbed gait variables in Nf1+/R681X adults tended to be the most highly significant variables during development, such as stride length, which was significantly increased in both development and adulthood as compared to WT littermates (Fig. 5). These findings demonstrate that Nf1+/R681X mice exhibited multiple spatial, temporal, and postural gait abnormalities in gait subcomponents that persist into adulthood, while the complete deletion (CD) model had developmental disruptions in gait that were largely resolved by adulthood
Summary
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). They represent an opportunity to define the consequences of NDD-associated genetic mutations on the development and function of well-understood CNS circuits, and to determine whether distinct neurogenetic disorders might have some shared consequences These more accessible phenotypes could be used to judge both the efficacy of NDD treatments as well as the effect of long-term use of these therapeutics. The existence of a common gait phenotype between multiple NDDs has not been established. This is due to the difficulty of performing longitudinal human studies and the confounding effects of genetic heterogeneity in clinical populations
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