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Updated: Dec 23, 2025
Low-Cost Gait Analysis for Behavioral Phenotyping of Mouse Models of Neuromuscular Disease
Published on: July 18, 2019
Motor transmission defects with sex differences in a new mouse model of mild spinal muscular atrophy
Marc-Olivier Deguise1, Yves De Repentigny2, Alexandra Tierney2
1Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Background:
Mouse models of mild spinal muscular atrophy (SMA) have been extremely challenging to generate. This paucity of model systems has limited our understanding of pathophysiological events in milder forms of the disease and of the effect of SMN depletion during aging.
Methods:
A mild mouse model of SMA, termed Smn2B/-;SMN2+/-, was generated by crossing Smn-/-;SMN2 and Smn2B/2B mice. This new model was characterized using behavioral testing, histology, western blot, muscle-nerve electrophysiology as well as ultrasonography to study classical SMA features and extra-neuronal involvement.
Findings:
Smn2B/-;SMN2+/- mice have normal survival, mild but sustained motor weakness, denervation and neuronal/neuromuscular junction (NMJ) transmission defects, and neurogenic muscle atrophy that are more prominent in male mice. Increased centrally located nuclei, intrinsic contractile and relaxation muscle defects were also identified in both female and male mice, with some male predominance. There was an absence of extra-neuronal pathology.
Interpretation:
The Smn2B/-;SMN2+/- mouse provides a model of mild SMA, displaying some hallmark features including reduced weight, sustained motor weakness, electrophysiological transmission deficit, NMJ defects, and muscle atrophy. Early and prominent increase central nucleation and intrinsic electrophysiological deficits demonstrate the potential role played by muscle in SMA disease. The use of this model will allow for the understanding of the most susceptible pathogenic molecular changes in motor neurons and muscles, investigation of the effects of SMN depletion in aging, sex differences and most importantly will provide guidance for the currently aging SMA patients treated with the recently approved genetic therapies.
Funding:
This work was supported by Cure SMA/Families of SMA Canada (grant numbers KOT-1819 and KOT-2021); Muscular Dystrophy Association (USA) (grant number 575466); and Canadian Institutes of Health Research (CIHR) (grant number PJT-156379).
Insights
A new mouse model for mild spinal muscular atrophy (SMA) exhibits motor weakness and muscle atrophy, aiding research into aging effects and sex differences in SMA patients. This model offers insights into disease mechanisms and genetic therapies.
Area of Science:
- Neuroscience
- Genetics
- Muscle Biology
Background:
- Developing mouse models for mild spinal muscular atrophy (SMA) has been challenging.
- Limited models hinder understanding of SMA pathophysiology and SMN depletion during aging.
Purpose of the Study:
- To generate and characterize a novel mouse model for mild spinal muscular atrophy (SMA).
- To investigate SMA features, including motor neuron and muscle involvement, and potential sex differences.
Main Methods:
- Generated a mild SMA mouse model (Smn2B/-;SMN2+/-) by crossing specific Smn mouse lines.
- Utilized behavioral testing, histology, western blot, electrophysiology, and ultrasonography for characterization.
Main Results:
- The Smn2B/-;SMN2+/- mice display normal survival, mild motor weakness, denervation, NMJ defects, and neurogenic muscle atrophy, more pronounced in males.
- Increased central nucleation and intrinsic muscle defects were observed in both sexes, with male predominance.
- No extra-neuronal pathology was detected.
Conclusions:
- The Smn2B/-;SMN2+/- mouse serves as a valuable model for mild SMA, recapitulating key features like motor deficits and muscle atrophy.
- This model facilitates research into SMN depletion's effects on aging, sex differences, and guides therapeutic strategies for SMA patients.
