title: Relative contributions of severe dopaminergic neuron ablation and dopamine depletion to cognitive impairment.
abstract: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and produces a movement disorder and cognitive impairment that becomes more extensive with the duration of the disease. To what extent cognitive impairment in advanced PD can be attributed to severe loss of dopamine (DA) signaling is not well understood. Furthermore, it is unclear if the loss of DA neurons contributes to the cognitive impairment caused by the reduction in DA signaling. We generated genetic mouse models with equally severe chronic loss of DA achieved by either extensive ablation of DA neurons or inactivation of DA synthesis from preserved neurons and compared their motor and cognitive performance. Motor behaviors were equally blunted in both models, but we observed that DA neuron ablation caused more severe cognitive deficits than DA depletion. Both models had marked deficits in cue-discrimination learning. Yet, deficits in cue-discrimination learning were more severe in mice with DA neuron ablation and only mice with DA neuron ablation had drastically impaired performance in spatial learning, spatial memory and object memory tests. These results indicate that while a severe reduction in DA signaling results in motor and cognitive impairments, the loss of DA neurons promotes more extensive cognitive deficits and suggest that a loss of additional factors that depend on DA neurons may participate in the progressive cognitive decline found in patients with PD.
authors.affiliation: Department of Pathology, University of Washington School of Medicine, University of Washington, Box 357470, Seattle, WA 98195, USA.
authors.forename: R Garrett
authors.initials: RG
authors.lastname: Morgan
authors.affiliation: Department of Pathology, University of Washington School of Medicine, University of Washington, Box 357470, Seattle, WA 98195, USA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Gibbs
authors.affiliation: Department of Pathology, University of Washington School of Medicine, University of Washington, Box 357470, Seattle, WA 98195, USA.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Melief
authors.affiliation: Department of Pathology, University of Washington School of Medicine, University of Washington, Box 357470, Seattle, WA 98195, USA.
authors.forename: Nadia O
authors.initials: NO
authors.lastname: Postupna
authors.affiliation: Department of Pathology, University of Washington School of Medicine, University of Washington, Box 357470, Seattle, WA 98195, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Sherfield
authors.affiliation: Department of Pathology, University of Washington School of Medicine, University of Washington, Box 357470, Seattle, WA 98195, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Department of Pathology, University of Washington School of Medicine, University of Washington, Box 357470, Seattle, WA 98195, USA.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Pathology, University of Washington School of Medicine, University of Washington, Box 357470, Seattle, WA 98195, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Department of Biochemistry, University of Washington School of Medicine, University of Washington, Box 357350, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington School of Medicine, University of Washington, Box 357350, Seattle, WA 98195, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
authors.affiliation: Department of Pathology, University of Washington School of Medicine, University of Washington, Box 357470, Seattle, WA 98195, USA. Electronic address: mdarvas@uw.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Darvas
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000235:genetics; D001552:Benzazepines / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004167:Diphtheria Toxin / Q000633:toxicity; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D000077487:Pramipexole; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency / Q000235:genetics
chemical_list: D001552:Benzazepines; D052160:Benzothiazoles; D004167:Diphtheria Toxin; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; C067113:SK&F 81297; D000077487:Pramipexole; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Animal model; Dementia; Dopamine loss; Neurodegeneration; Parkinson's disease