Phenotypic analysis of mouse models of human diseases is essential to understanding the underlying disease mechanisms and to developing therapeutics. Many models of neurodegenerative diseases are associated with motor dysfunction, a powerful readout for the disease. We describe here a set of measures to quantitatively monitor early disease onset and progression. We named this set of rules qMotor because it enables sensitive, robust and quantitative measurement of motor performance in 3 d. qMotor can be used to assess early disease onset, before paralysis, as well as disease progression in diverse mouse models, and can be exploited to define robust and humane experimental end points, thereby reducing animal suffering. As an example, we apply qMotor to SOD1G93A transgenic mice. Early studies with the original transgenic SOD1G93A mice in the hybrid background (B6SJL-Tg(SOD1-G93A) have been criticized because of high noise in this mixed background and because of inadequate study designs. We applied qMotor in SOD1G93A transgenic mice in an inbred C57BL/6J background, hereafter called iSOD1G93A mice, and show a remarkably robust and consistent phenotype in this line that we use to evaluate a therapeutic approach. qMotor is a protocol generically applicable to different mouse models.
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We thank A. Devoy, for the generous gift of the iSOD1G93A C57BL/6J line and for her support in establishing the colony in our facility; L. Wrabetz and M. D'Antonio of the San Raffaele Institute, for the CMT-1B mice; the LMB mouse facility; A. Segonds-Pichon, for advice on statistical analyses; members of the Bertolotti lab for discussions; and J. Watson, for comments on the manuscript. A.B. is an honorary fellow of the Clinical Neurosciences Department of Cambridge University. This work was supported by the Medical Research Council and the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant 309516.
The authors declare no competing financial interests.
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a,b, Rotarod analysis of wild-type or CMT-1B females (a) or males (b) mice of indicated age following orally gavage (twice daily) with Sephin1 (1 mg/kg) or vehicle. Data are means of three trails performed on the same day ± SEM (n=4-8). The data shown here are the same as in Figure 1 but the analysis were performed separating genders. No samples, mice or data points were excluded from the analyses. All data shown were collected while conforming to governmental and institutional guidelines for care and use of laboratory animals. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001; (males F(1,14)=13.55, p=0.0025; females F(1,14)=9.38, p=0.0091).
a,b, Rotarod analysis of wild-type or iSOD1G93A mice of indicated age and gender treated orally with Sephin1 (5 mg/kg) or vehicle once a day from 28 days of age. Data are means of 3 trails performed on the same day ± SEM (n=2-3). The data shown here are the same as in Figure 2 but the analysis were performed separating genders. No samples, mice or data points were excluded from the analyses. All data shown were collected while conforming to governmental and institutional guidelines for care and use of laboratory animals.
a-c, Rotarod analysis of wild-type or iSOD1G93A mice of indicated age (days). (a): mixed genders, (b): females and (c) males. Data are means of 3 trials performed on three consecutive days ± SEM (n=11-15). No samples, mice or data points were excluded from the analyses. All data shown were collected while conforming to governmental and institutional guidelines for care and use of laboratory animals. All data shown were collected while conforming to governmental and institutional guidelines for care and use of laboratory animals. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001; (a. F(1,24)=199.0, p<0.0001; b. F(1,12)=104.3, p<0.0001, c. F(1,10)=114.1, p<0.0001).
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Luh, L., Das, I. & Bertolotti, A. qMotor, a set of rules for sensitive, robust and quantitative measurement of motor performance in mice. Nat Protoc 12, 1451–1457 (2017). https://doi.org/10.1038/nprot.2017.062
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