title: Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice.
abstract: 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 (0.01-1mg/kg). Chronic treatment with concentrations of rotenone up to 0.8mg/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 0.8mg/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 (0.1mg/kg) concentration. Even lower concentrations (0.01mg/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.
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Plasticity, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Martella
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Plasticity, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Madeo
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Maltese
authors.affiliation: IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Plasticity, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Vanni
authors.affiliation: IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Plasticity, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Puglisi
authors.affiliation: IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Plasticity, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ferraro
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Schirinzi
authors.affiliation: IRCCS Casa Sollievo della Sofferenza, Mendel Laboratory, San Giovanni Rotondo, Italy.
authors.forename: E M
authors.initials: EM
authors.lastname: Valente
authors.affiliation: Department of Neuroscience & Imaging, University G. d'Annunzio of Chieti, Pescara, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Bonanni
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.affiliation: IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Plasticity, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mandolesi
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Plasticity, Rome, Italy.
authors.forename: N B
authors.initials: NB
authors.lastname: Mercuri
authors.affiliation: IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Plasticity, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bonsi
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; IRCCS Fondazione Santa Lucia, Laboratory of Neurophysiology and Plasticity, Rome, Italy. Electronic address: pisani@uniroma2.it.
authors.forename: A
authors.initials: A
authors.lastname: Pisani
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006579:Heterozygote; D017774:Long-Term Potentiation / Q000187:drug effects; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects / Q000235:genetics*; D012402:Rotenone / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D011494:Protein Kinases; D012402:Rotenone; D000099202:PTEN-Induced Putative Kinase
keywords: Electrophysiology; Mitochondria; PINK1 heterozygous mutations; Parkinson's disease; Rotenone; Striatum; Synaptic plasticity