Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice
- Tohru Kitada*,
- Antonio Pisani†,
- Douglas R. Porter‡,
- Hiroo Yamaguchi*,
- Anne Tscherter†,
- Giuseppina Martella†,
- Paola Bonsi†,
- Chen Zhang*,
- Emmanuel N. Pothos‡, and
- Jie Shen*,§
- *Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115;
- †Department of Neuroscience, University of Rome Tor Vergata and Fondazione Santa Lucia, 00133 Rome, Italy; and
- ‡Department of Pharmacology and Experimental Therapeutics and Program in Neuroscience, Tufts University School of Medicine, Boston, MA 02111
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Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX, and approved May 1, 2007 (received for review March 23, 2007)
Abstract
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.
Footnotes
- §To whom correspondence should be addressed at: Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, New Research Building, Room 636E, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail: jshen{at}rics.bwh.harvard.edu
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Author contributions: A.P., E.N.P., and J.S. designed research; T.K., D.R.P., H.Y., A.T., G.M., P.B., and C.Z. performed research; T.K., A.P., H.Y., C.Z., E.N.P., and J.S. analyzed data; and A.P., E.N.P., and J.S. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0702717104/DC1.
- Abbreviations:
- DA,
- dopamine;
- EPSC,
- excitatory postsynaptic current;
- HFS,
- high-frequency stimulation;
- LTD,
- long-term depression;
- LTP,
- long-term potentiation;
- MS,
- medium-sized spiny;
- PD,
- Parkinson's disease;
- SNpc,
- pars compacta of the substantia nigra;
- TH,
- tyrosine hydroxylase.
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Freely available online through the PNAS open access option.
- © 2007 by The National Academy of Sciences of the USA
