Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein

Abstract

Accumulation of alpha-synuclein in brain is a hallmark of synucleinopathies, neurodegenerative diseases that include Parkinson's disease. Mice overexpressing alpha-synuclein under the Thy-1 promoter (ASO) show abnormal accumulation of alpha-synuclein in cortical and subcortical regions of the brain, including the substantia nigra. We examined the motor deficits in ASO mice with a battery of sensorimotor tests that are sensitive to alterations in the nigrostriatal dopaminergic system. Male wild-type and ASO mice were tested every 2 months for 8 months for motor performance and coordination on a challenging beam, inverted grid, and pole, sensorimotor deficits in an adhesive removal test, spontaneous activity in a cylinder, and gait. Fine motor skills were assessed by the ability to grasp cotton from a bin. ASO mice displayed significant impairments in motor performance and coordination and a reduction in spontaneous activity as early as 2 months of age. Motor performance and coordination impairments became progressively worse with age and sensorimotor deficits appeared at 6 months. Fine motor skills were altered at 4 months and worsened at 8 months. These data indicate that overexpression of alpha-synuclein induced an early and progressive behavioral phenotype that can be detected in multiple tests of sensorimotor function. These behavioral deficits provide a useful way to assess novel drug therapy in genetic models of synucleinopathies.

Figure 1.

ASO mice were weighed before behavioral testing at 2, 4, 6, and 8 months of age. ASO (n = 7) mice weighed significantly lessthan wild-type (n = 17) mice at all ages. Values are expressed as mean weight (in grams) ± SEM; ^**p < 0.01 compared with wild type.

Figure 2.

Motor performance and coordination was measured in ASO (n = 7) and wild-type (n = 17) mice using the challenging beam. Errors per step (A), number of steps (B), and time to traverse (C) were measured at 2, 4, 6, and 8 months of age. ASO mice made more errors and steps and took longer to traverse the beam compared with wild-type mice. In addition, ASO impairments worsened over time. Values are expressed as mean ± SEM. ^*p < 0.05 and ^**p < 0.01, compared with wild-type mice at the same age; ^ΔΔp < 0.01, compared with previous ages tested within the ASO group.

Figure 3.

Adhesive removal was measured in ASO (n = 7) and wild-type (n = 17) mice at 2, 4, 6, and 8 months of age. At 6 months of age, ASO mice were significantly slower to respond to sensory stimuli compared with wild-type mice (A). The time from stimulus contact to stimulus removal did not differ between ASO and wild-type mice (B). Values are expressed as means ± SEM. ^*p < 0.05, compared with wild-type mice.

Figure 4.

Spontaneous activity in ASO (n = 7) and wild-type (n = 17) mice at 2, 4, 6, and 8 months of age. Rearing (A), forelimb (B) and hindlimb (C) steps, and time spent grooming (D) were measured. ASO mice were less active in all measures compared with wild-type mice. Values are expressed as mean ± SEM. ^*p < 0.05 and ^**p < 0.01, compared with wild-type mice.

Figure 5.

Bin cotton use in ASO and wild-type mice at 4 (A; n = 8) and 8 (B, C; n = 12) months of age. Separate groups of ASO mice shredded significantly less cotton compared with wild-type mice. Cotton was placed inside the cage of 8-month-old ASO mice to demonstrate that ASO mice can make nests (C). Values are expressed as mean ± SEM. ^*p < 0.05 and ^**p < 0.01, compared with wild-type mice.