Impaired dopamine release and synaptic plasticity in the striatum of parkin-/- mice.
Parkin is the most common causative gene of juvenile and early-onset familial Parkinson's diseases and is thought to function as an E3 ubiquitin ligase in the ubiquitin-proteasome system. However, it remains unclear how loss of Parkin protein causes dopaminergic dysfunction and nigral neurodegeneration. To investigate the pathogenic mechanism underlying these mutations, we used parkin-/- mice to study its physiological function in the nigrostriatal circuit. Amperometric recordings showed decreases in evoked dopamine release in acute striatal slices of parkin-/- mice and reductions in the total catecholamine release and quantal size in dissociated chromaffin cells derived from parkin-/- mice. Intracellular recordings of striatal medium spiny neurons revealed impairments of long-term depression and long-term potentiation in parkin-/- mice, whereas long-term potentiation was normal in the Schaeffer collateral pathway of the hippocampus. Levels of dopamine receptors and dopamine transporters were normal in the parkin-/- striatum. These results indicate that Parkin is involved in the regulation of evoked dopamine release and striatal synaptic plasticity in the nigrostriatal pathway, and suggest that impairment in evoked dopamine release may represent a common pathophysiological change in recessive parkinsonism.
Kitada
Tohru
T
Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Pisani
Antonio
A
Karouani
Maha
M
Haburcak
Marian
M
Martella
Giuseppina
G
Tscherter
Anne
A
Platania
Paola
P
Wu
Bei
B
Pothos
Emmanuel N
EN
Shen
Jie
J
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D004558:Electric Stimulation; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D036881:Long-Term Synaptic Depression / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine