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Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders

View ORCID ProfileRachel M. Rahn, Claire T. Weichselbaum, David H. Gutmann, View ORCID ProfileJoseph D. Dougherty, View ORCID ProfileSusan E. Maloney
doi: https://doi.org/10.1101/2020.10.12.336586
Rachel M. Rahn
1Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
2Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
3Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
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Claire T. Weichselbaum
1Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
2Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
4Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, USA
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David H. Gutmann
4Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, USA
5Department of Neurology; Washington University School of Medicine, St. Louis, MO, USA
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Joseph D. Dougherty
1Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
2Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
4Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, USA
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Susan E. Maloney
1Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
4Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, USA
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  • For correspondence: maloneys@wustl.edu
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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.

Lay Summary Gait 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.

  • Gait
  • Williams Syndrome
  • Neurofibromatosis Type 1
  • mice
  • precision medicine
  • neurodevelopmental disorders

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 12, 2020.
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Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders
Rachel M. Rahn, Claire T. Weichselbaum, David H. Gutmann, Joseph D. Dougherty, Susan E. Maloney
bioRxiv 2020.10.12.336586; doi: https://doi.org/10.1101/2020.10.12.336586
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Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders
Rachel M. Rahn, Claire T. Weichselbaum, David H. Gutmann, Joseph D. Dougherty, Susan E. Maloney
bioRxiv 2020.10.12.336586; doi: https://doi.org/10.1101/2020.10.12.336586

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