Abstract
The manifestations of Parkinson's disease are caused by reduced dopaminergic innervation of the striatum. Loss-of-function mutations in the DJ-1 gene cause early-onset familial parkinsonism. To investigate a possible role for DJ-1 in the dopaminergic system, we generated a mouse model bearing a germline disruption of DJ-1. Although DJ-1(-/-) mice had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine overflow in the striatum was markedly reduced, primarily as a result of increased reuptake. Nigral neurons lacking DJ-1 were less sensitive to the inhibitory effects of D2 autoreceptor stimulation. Corticostriatal long-term potentiation was normal in medium spiny neurons of DJ-1(-/-) mice, but long-term depression (LTD) was absent. The LTD deficit was reversed by treatment with D2 but not D1 receptor agonists. Furthermore, DJ-1(-/-) mice displayed hypoactivity in the open field. Collectively, our findings suggest an essential role for DJ-1 in dopaminergic physiology and D2 receptor-mediated functions.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
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Age Factors
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Animals
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Behavior, Animal
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Blotting, Southern / methods
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Blotting, Western / methods
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Cell Count
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Cerebral Cortex / cytology
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Cerebral Cortex / physiology
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Disease Models, Animal
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Dopamine / deficiency*
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Dopamine Agonists / pharmacology
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Dopamine Plasma Membrane Transport Proteins
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Electric Stimulation / methods
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Electrochemistry / methods
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Germ-Line Mutation
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Humans
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Hypokinesia / physiopathology*
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Immunohistochemistry / methods
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins / metabolism
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Membrane Transport Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Nerve Tissue Proteins / metabolism
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Neurons / physiology
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Oncogene Proteins / physiology*
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Parkinsonian Disorders / genetics
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Parkinsonian Disorders / metabolism*
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Protein Deglycase DJ-1
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Quinpirole / pharmacology
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RNA, Messenger / biosynthesis
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Radioligand Assay / methods
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Receptors, Dopamine D2 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Substantia Nigra / cytology
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Substantia Nigra / drug effects
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Substantia Nigra / metabolism*
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Tyrosine 3-Monooxygenase / metabolism
Substances
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Dopamine Agonists
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Dopamine Plasma Membrane Transport Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Oncogene Proteins
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RNA, Messenger
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Receptors, Dopamine D2
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Quinpirole
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2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
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Tyrosine 3-Monooxygenase
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PARK7 protein, human
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Protein Deglycase DJ-1
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Dopamine