Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1.
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.
Pubmed ID: 15721235 RIS Download
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine | Age Factors | Animals | Behavior, Animal | Blotting, Southern | Blotting, Western | Cell Count | Cerebral Cortex | Disease Models, Animal | Dopamine | Dopamine Agonists | Dopamine Plasma Membrane Transport Proteins | Electric Stimulation | Electrochemistry | Excitatory Postsynaptic Potentials | Germ-Line Mutation | Humans | Hypokinesia | Immunohistochemistry | In Vitro Techniques | Intracellular Signaling Peptides and Proteins | Membrane Glycoproteins | Membrane Transport Proteins | Mice | Mice, Inbred C57BL | Mice, Transgenic | Nerve Tissue Proteins | Neurons | Oncogene Proteins | Parkinsonian Disorders | Protein Deglycase DJ-1 | Quinpirole | RNA, Messenger | Radioligand Assay | Receptors, Dopamine D2 | Reverse Transcriptase Polymerase Chain Reaction | Substantia Nigra | Tyrosine 3-Monooxygenase