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The Journal of Neuroscience, October 20, 2004, 24(42):9434-9440; doi:10.1523/JNEUROSCI.3080-04.2004

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Neurobiology of Disease
Early and Progressive Sensorimotor Anomalies in Mice Overexpressing Wild-Type Human -Synuclein

Sheila M. Fleming,¹ Jonathan Salcedo,¹ Pierre-Olivier Fernagut,¹ Edward Rockenstein,³ Eliezer Masliah,³ Michael S. Levine,² and Marie-Françoise Chesselet¹

¹Departments of Neurology and Neurobiology, ²The Mental Retardation Research Center, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095-1769, and ³Department of Neuroscience, University of California San Diego, La Jolla, California 92093-0624

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.

Key words: basal ganglia; behavior; movement; Parkinson; nigrostriatal; phenotype

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Received July 28, 2004; revised September 2, 2004; accepted September 3, 2004.

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