Early and Progressive Sensorimotor Anomalies in Mice Overexpressing Wild-Type Human α-Synuclein

Abstract

Accumulation of ␣-synuclein in brain is a hallmark of synucleinopathies, neurodegenerative diseases that include Parkinson's disease. Mice overexpressing ␣-synuclein under the Thy-1 promoter (ASO) show abnormal accumulation of ␣-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 ␣-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.

Behavioral and histopathological consequences of paraquat intoxication in mice: Effects of α‐synuclein over‐expression

“…As previously reported (Fleming et al, 2004), behavioral assessment of sensorimotor function revealed impaired performance of Thy1-aSYN mice. On the beam traversal task, there was a significant effect of genotype (F (1,55) = 79.96, P < 0.0001) and Thy1-aSYN mice made significantly more errors per step than their WT counterparts (P < 0.01, Fig.…”

“…Challenging beam traversal-The challenging beam traversal test was performed as previously described (Fleming et al, 2004). The plexiglas beam (Plastics Zone, Woodland Hills, CA) was made of four sections (25 cm length) starting at a width of 3.5 cm and gradually narrowing to 0.5 cm × 1 cm increments.…”

“…Pole test-The pole test was performed according to Matsuura et al (1997) with minor modifications (Fleming et al, 2004). The mouse was placed head upward on the top of a vertical wooden rough-surfaced pole (diameter: 1 cm, height: 50 cm).…”

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

“…The Murine Thy-1 Promoter Importantly, in contrast to other lines of mice using the Thy-1 promoter [25], the Thy1-aSyn mice of line 61 do not exhibit obvious motor neuron pathology [21] and do not show motor neuron deficits in behavioral tests [26]. The absence of motor neuron degeneration in Thy1-aSyn mice is critically important, as their behavioral deficits are more likely to reflect impairments that are relevant to PD and single out the Thy1-aSyn mice as particularly suitable for preclinical drug testing, described as follows.…”

Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse

“…The motor response to sensory stimuli was measured with a stimulation test developed for rats (Marshall and Gotthelf, 1979;Schallert et al, 1983) and adopted for mice (Fleming et al, 2004). Small adhesive stimuli (50 mm 2 ) were placed on the snout of the mouse in their home cages.…”