Gait dynamics in mouse models of Parkinson's disease and Huntington's disease

Abstract

Background: Gait is impaired in patients with Parkinson's disease (PD) and Huntington's disease (HD), but gait dynamics in mouse models of PD and HD have not been described. Here we quantified temporal and spatial indices of gait dynamics in a mouse model of PD and a mouse model of HD.

Methods: Gait indices were obtained in C57BL/6J mice treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg/day for 3 days) for PD, the mitochondrial toxin 3-nitropropionic acid (3NP, 75 mg/kg cumulative dose) for HD, or saline. We applied ventral plane videography to generate digital paw prints from which indices of gait and gait variability were determined. Mice walked on a transparent treadmill belt at a speed of 34 cm/s after treatments.

Results: Stride length was significantly shorter in MPTP-treated mice (6.6 +/- 0.1 cm vs. 7.1 +/- 0.1 cm, P < 0.05) and stride frequency was significantly increased (5.4 +/- 0.1 Hz vs. 5.0 +/- 0.1 Hz, P < 0.05) after 3 administrations of MPTP, compared to saline-treated mice. The inability of some mice treated with 3NP to exhibit coordinated gait was due to hind limb failure while forelimb gait dynamics remained intact. Stride-to-stride variability was significantly increased in MPTP-treated and 3NP-treated mice compared to saline-treated mice. To determine if gait disturbances due to MPTP and 3NP, drugs affecting the basal ganglia, were comparable to gait disturbances associated with motor neuron diseases, we also studied gait dynamics in a mouse model of amyotrophic lateral sclerosis (ALS). Gait variability was not increased in the SOD1 G93A transgenic model of ALS compared to wild-type control mice.

Conclusion: The distinct characteristics of gait and gait variability in the MPTP model of Parkinson's disease and the 3NP model of Huntington's disease may reflect impairment of specific neural pathways involved.

Figure 1

Ventral view of walking saline-treated mouse. A. Two images depicting the ventral view of a saline-treated C57BL/6J mouse on a transparent treadmill belt walking at a speed of 34 cm/s. The example on the left depicts full stance for the right hind limb, and the example on the right depicts sequential full stance for the left hind limb. Cartesian coordinates are used to determine stance width and paw placement angles for the forelimbs and hind limbs. B. Representative gait signals of the left forelimb and right hind limb of a saline-treated C57BL/6J mouse walking at a speed of 34 cm/s. Duration of stride, stance, and swing are indicated for the right hind limb. Duration of braking and propulsion are indicated for the left fore limb.

Figure 2

Gait signals in a MPTP-treated mouse. Gait signal of the right hind limb of a MPTP-treated mouse superimposed over the gait signal of the right hind limb of a saline-treated mouse. Stride frequency was higher in MPTP-treated mice compared to saline treated mice. Stance duration and swing duration were shorter in MPTP-treated mice compared to saline-treated mice.

Figure 3

Stride time dynamics. Examples of stride time (gait cycle duration) in MPTP-treated, 3NP-treated, and saline-treated mice of forelimbs (left panels) and hind limbs (right panels). In saline-treated animals, forelimb stride variability was higher than hind limb stride variability. MPTP-treated and 3NP-treated mice exhibited significantly higher stride variability. The coefficient of variation (CV), a measure of stride-to-stride variability, was highest in the forelimbs of 3NP-treated mice.

Figure 4

Ventral view of a 3NP-treated mouse attempting to walk. A. The ventral view of a 3NP-treated mouse attempting to walk on the treadmill belt moving at a speed of 34 cm/s but failing to engage the hind limbs in coordinated stepping. This animal braced its hind paws onto the base of the sidewalls of the walking compartment avoiding the moving treadmill belt. Only the forelimbs execute coordinated stepping sequences. B. Gait signals of the left and right forelimbs of a 3NP-treated mouse demonstrating coordinated stepping, despite hind limb failure of stepping. The signals of left and right hind limbs are not coordinated and reflect artefacts associated with the belt contacting the braced paws.