TY - JOUR
T1 - Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice
AU - Martella, G.
AU - Madeo, Graziella
AU - Maltese, Marta
AU - Vanni, Valentina
AU - Puglisi, F.
AU - Ferraro, Elisabetta
AU - Schirinzi, T.
AU - Valente, Enza Maria
AU - Bonanni, Laura
AU - Shen, J.
AU - Mandolesi, Georgia
AU - Mercuri, Nicola Biagio
AU - Bonsi, Paola
AU - Pisani, Antonio
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - Electrophysiology
KW - Mitochondria
KW - Parkinson's disease
KW - PINK1 heterozygous mutations
KW - Rotenone
KW - Striatum
KW - Synaptic plasticity
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UR - http://www.scopus.com/inward/citedby.url?scp=84960848269&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2015.12.020
DO - 10.1016/j.nbd.2015.12.020
M3 - Article
VL - 91
SP - 21
EP - 36
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
ER -