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 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 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 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. These 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.

Hybrid offspring of C57BL/6J mice exhibit improved properties for neurobehavioral research

“…To provide a quantitative description of the HYB, we supplemented the array of standard assays with gait assessment and home cage behavior. The gait of all strains was inconsistent with abnormalities seen in motor disorders (Preisig et al, 2016; Rahn et al, 2021), yet every strain exhibited distinct gait patterns that were largely preserved upon aging. In addition, we observed apparent inter-strain differences of daily conduct in the home cage, including distinct time division between sheltering, wheel running, and feeding.…”

“…To characterize neuropsychiatric phenotypes and cognitive performance, we tested 9-month-old mice using five assays (Table S1). Anxiety-like behavior was studied using the elevated plus maze (Rodgers and Dalvi, 1997) and quantified by a "contra-anxiety index" that ranges from -1 to 1, defined as time spent in (open-closed)/(open+closed) arms. Indices closer to one indicate that more time was spent in the two "open" arms, corresponding to reduced anxiety-like behavior.…”

“…Elevated plus maze. The elevated plus maze is used to evaluate anxietylike behavior based on the natural uneasiness of rodents towards open, elevated fields (Rodgers and Dalvi, 1997;Crawley, 2000;Komada et al, 2008). The apparatus consists of a four-armed platform resembling a ''+'' shape, positioned 40 cm above the floor.…”

Hybrid Offspring of C57BL/6J Mice Exhibit Improved Properties for Neurobehavioral Research

“…A second challenge is to ensure the stability of the tested phenotype under the null condition throughout the study period. In many cases, the effects of a given manipulation are studied over weeks to months (Prevot et al, 2019;Namdar et al, 2020;Rahn et al, 2021). Deterioration of control phenotypic behavior could confound potential manipulation-based inter-group differences.…”

Gait as a Quantitative Translational Outcome Measure in Angelman Syndrome

“…Our study showcases translational and longitudinal use of quantitative motor metrics for a genetic NDD. Clinically, quantitative gait research has gained traction across many NDDs and the idea to tailor attention on gait in preclinical studies is now also gaining momentum (IDDRC working group, AGENDA working group, personal communications) for Rett syndrome, neurofibromatosis, Down syndrome, and other NDDs (Hampton et al, 2004;Jequier Gygax et al, 2020;Kennedy et al, 2020;Layne et al 2018;Rahn et al, 2020;Summers et al, 2015;Wilson et al, 2020). Data from our work showed analogous measures of gait phenotypes in rodents that are being quantified currently in AS clinics (Jessica Duis MD, personal communication).…”