Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice

G. Martella, Graziella Madeo, Marta Maltese, Valentina Vanni, F. Puglisi, Elisabetta Ferraro, T. Schirinzi, Enza Maria Valente, Laura Bonanni, J. Shen, Georgia Mandolesi, Nicola Biagio Mercuri, Paola Bonsi, Antonio Pisani

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Heterozygous mutations in the PINK1 gene are considered a susceptibility factor to develop early-onset Parkinson's disease (PD), as supported by dopamine hypometabolism in asymptomatic mutation carriers and subtle alterations of dopamine-dependent striatal synaptic plasticity in heterozygous PINK1 knockout (PINK1+/-) mice. The aim of the present study was to investigate whether exposure to low-dose rotenone of heterozygous PINK1+/- mice, compared to their wild-type PINK1+/+ littermates, could impact on dopamine-dependent striatal synaptic plasticity, in the absence of apparent structural alterations.Mice were exposed to a range of concentrations of rotenone (0.01-1 mg/kg). Chronic treatment with concentrations of rotenone up to 0.8 mg/kg did not cause manifest neuronal loss or changes in ATP levels both in the striatum or substantia nigra of PINK1+/- and PINK1+/+ mice. Moreover, rotenone (up to 0.8 mg/kg) treatment did not induce mislocalization of the mitochondrial membrane protein Tom20 and release of cytochrome c in PINK1+/- striata. Accordingly, basic electrophysiological properties of nigral dopaminergic and striatal medium spiny neurons (MSNs) were normal. Despite the lack of gross alterations in neuronal viability in chronically-treated PINK1+/-, a complete loss of both long-term depression (LTD) and long-term potentiation (LTP) was recorded in MSNs from PINK1+/- mice treated with a low rotenone (0.1 mg/kg) concentration. Even lower concentrations (0.01 mg/kg) blocked LTP induction in heterozygous PINK1+/- MSNs compared to PINK1+/+ mice. Of interest, chronic pretreatment with the antioxidants alpha-tocopherol and Trolox, a water-soluble analog of vitamin E and powerful antioxidant, rescued synaptic plasticity impairment, confirming that, at the doses we utilized, rotenone did not induce irreversible alterations.In this model, chronic exposure to low-doses of rotenone was not sufficient to alter mitochondrial integrity and ATP production, but profoundly impaired the expression of long-term plasticity at corticostriatal synapses in PINK1 heterozygous knockout mice, suggesting that disruption of synaptic plasticity may represent an early feature of a pre-manifesting state of the disease, and a potential tool to test novel neuroprotective agents.

Original languageEnglish
Pages (from-to)21-36
Number of pages16
JournalNeurobiology of Disease
Publication statusPublished - Jul 1 2016


  • Electrophysiology
  • Mitochondria
  • Parkinson's disease
  • PINK1 heterozygous mutations
  • Rotenone
  • Striatum
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neurology


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