Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice.
Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1(-/-) mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1(-/-) mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1(-/-) mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or l-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.
Kitada
Tohru
T
Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Pisani
Antonio
A
Porter
Douglas R
DR
Yamaguchi
Hiroo
H
Tscherter
Anne
A
Martella
Giuseppina
G
Bonsi
Paola
P
Zhang
Chen
C
Pothos
Emmanuel N
EN
Shen
Jie
J
D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000201:enzymology / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics; D017729:Presynaptic Terminals / Q000201:enzymology / Q000502:physiology*; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
D004298:Dopamine; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase