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, Jie Shen

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    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.

    Original languageEnglish
    Pages (from-to)11441-11446
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume104
    Issue number27
    DOIs
    Publication statusPublished - Jul 3 2007

    All Science Journal Classification (ASJC) codes

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    Kitada, T., Pisani, A., Porter, D. R., Yamaguchi, H., Tscherter, A., Martella, G., Bonsi, P., Zhang, C., Pothos, E. N., & Shen, J. (2007). Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 104(27), 11441-11446. https://doi.org/10.1073/pnas.0702717104