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

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.

[1]  Alexander Storch,et al.  Early diagnosis of Parkinson’s disease , 2006, Journal of Neurology.

[2]  M. Chesselet,et al.  Alpha-synuclein and transgenic mouse models , 2004, Neurobiology of Disease.

[3]  D Oakes,et al.  Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease , 2003, Experimental Neurology.

[4]  Bryan L Roth,et al.  Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons* , 2003, Journal of Biological Chemistry.

[5]  M. Chesselet,et al.  Time course of early motor and neuropathological anomalies in a knock‐in mouse model of Huntington's disease with 140 CAG repeats , 2003, The Journal of comparative neurology.

[6]  Georg Auburger,et al.  Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation , 2003, Molecular and Cellular Neuroscience.

[7]  Kwang-Soo Kim,et al.  Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. , 2003, Brain research. Molecular brain research.

[8]  G. Miller,et al.  Grid performance test to measure behavioral impairment in the MPTP-treated-mouse model of parkinsonism , 2003, Journal of Neuroscience Methods.

[9]  H. Braak,et al.  Staging of brain pathology related to sporadic Parkinson’s disease , 2003, Neurobiology of Aging.

[10]  M. Jaber,et al.  Motor behaviour deficits and their histopathological and functional correlates in the nigrostriatal system of dopamine transporter knockout mice , 2003, Neuroscience.

[11]  A. Singleton,et al.  alpha-Synuclein locus triplication causes Parkinson's disease. , 2003, Science.

[12]  G. Miller,et al.  Detection of Behavioral Impairments Correlated to Neurochemical Deficits in Mice Treated with Moderate Doses of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , 2002, Experimental Neurology.

[13]  P. Brundin,et al.  Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line* , 2002, The Journal of Biological Chemistry.

[14]  Patrik Brundin,et al.  Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson's disease. , 2002, Human molecular genetics.

[15]  M. Chesselet,et al.  Early Motor Dysfunction and Striosomal Distribution of Huntingtin Microaggregates in Huntington's Disease Knock-In Mice , 2002, The Journal of Neuroscience.

[16]  M. Zigmond,et al.  Forced Nonuse in Unilateral Parkinsonian Rats Exacerbates Injury , 2002, The Journal of Neuroscience.

[17]  Makoto Hashimoto,et al.  Differential neuropathological alterations in transgenic mice expressing α‐synuclein from the platelet‐derived growth factor and Thy‐1 promoters , 2002, Journal of neuroscience research.

[18]  Howard J. Federoff,et al.  Behavioral and Neurochemical Effects of Wild-Type and Mutated Human α-Synuclein in Transgenic Mice , 2002, Experimental Neurology.

[19]  F. Tison,et al.  A simple method to measure stride length as an index of nigrostriatal dysfunction in mice , 2002, Journal of Neuroscience Methods.

[20]  M. Zigmond,et al.  A role for alpha-synuclein in the regulation of dopamine biosynthesis. , 2002, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  Joseph P Huston,et al.  Behavioral phenotyping of the MPTP mouse model of Parkinson's disease , 2001, Behavioural Brain Research.

[22]  G. M. Story,et al.  Evaluation of Nigrostriatal Dopaminergic Function in Adult +/+ and +/− BDNF Mutant Mice , 2001, Experimental Neurology.

[23]  M. Zigmond,et al.  Forced Limb-Use Effects on the Behavioral and Neurochemical Effects of 6-Hydroxydopamine , 2001, The Journal of Neuroscience.

[24]  R. Palmiter,et al.  Dopamine Production in the Caudate Putamen Restores Feeding in Dopamine-Deficient Mice , 2001, Neuron.

[25]  R. Schwarting,et al.  Evidence for a Dissociation between MPTP Toxicity and Tyrosinase Activity Based on Congenic Mouse Strain Susceptibility , 2001, Experimental Neurology.

[26]  R. Schwarting,et al.  MPTP Susceptibility in the Mouse: Behavioral, Neurochemical, and Histological Analysis of Gender and Strain Differences , 2000, Behavior genetics.

[27]  T. Schallert,et al.  CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury , 2000, Neuropharmacology.

[28]  Jacqueline N. Crawley,et al.  What's Wrong With My Mouse?: Behavioral Phenotyping of Transgenic and Knockout Mice , 2000 .

[29]  L. Mucke,et al.  Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. , 2000, Science.

[30]  P. Caroni,et al.  Neuropathology in mice expressing human alpha-synuclein. , 2000, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  Stephen B. Dunnett,et al.  Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington’s Disease Mutation , 1999, The Journal of Neuroscience.

[32]  P M Rossini,et al.  Neurophysiology of sensorimotor integration in Parkinson's disease. , 1998, Clinical neuroscience.

[33]  N. Ogawa,et al.  Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion , 1997, Journal of Neuroscience Methods.

[34]  Ryan J. Uitti,et al.  Early Detection of Parkinson’s Disease , 1996, Drugs & aging.

[35]  Francis Collins,et al.  Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia , 1996, Cell.

[36]  A J Lees,et al.  When did Ray Kennedy's Parkinson's disease begin? , 1992, Movement disorders : official journal of the Movement Disorder Society.

[37]  R. Drucker-Colín,et al.  A new motor test sensitive to aging and dopaminergic function , 1991, Journal of Neuroscience Methods.

[38]  W. Koller,et al.  The next frontier in Parkinson's disease , 1991, Neurology.

[39]  T. Schallert.  Aging‐dependent Emergence of Sensorimotor Dysfunction in Rats Recovered from Dopamine Depletion Sustained Early in Life a , 1988, Annals of the New York Academy of Sciences.

[40]  K. Mizukawa,et al.  MPTP-induced parkinsonian model in mice: biochemistry, pharmacology and behavior. , 1987, European neurology.

[41]  N. Ogawa,et al.  A simple quantitative bradykinesia test in MPTP-treated mice. , 1985, Research communications in chemical pathology and pharmacology.

[42]  I. Whishaw,et al.  Neonatal frontal lesions in hamsters impair species-typical behaviors and reduce brain weight and neocortical thickness. , 1985, Behavioral neuroscience.

[43]  T. Schallert,et al.  A behavior analysis of the offspring of "haloperidol-sensitive" and "haloperidol-resistant" gerbils. , 1983, Behavioral and neural biology.

[44]  T. Schallert,et al.  Posture-independent sensorimotor analysis of inter-hemispheric receptor asymmetries in neostriatum , 1983, Pharmacology Biochemistry and Behavior.

[45]  B. Svare,et al.  Strain-typical patterns of pregnancy-induced nestbuilding in mice: Maternal and experiential influences , 1982, Physiology & Behavior.

[46]  N. Lobaugh,et al.  Tactile extinction: Distinguishing between sensorimotor and motor asymmetries in rats with unilateral nigrostriatal damage , 1982, Pharmacology Biochemistry and Behavior.

[47]  C. B. Lynch.  Response to divergent selection for nesting behavior in Mus musculus. , 1980, Genetics.

[48]  J. Marshall,et al.  Sensory inattention in rats with 6-hydroxydopamine-induced degeneration of ascending dopaminergic neurons: Apomorphine-induced reversal of deficits , 1979, Experimental Neurology.

[49]  P. Teitelbaum,et al.  Compulsive, abnormal walking caused by anticholinergics in akinetic, 6-hydroxydopamine-treated rats. , 1978, Science.

[50]  P. Teitelbaum,et al.  Sensory Neglect Produced by Lateral Hypothalamic Damage , 1971, Science.