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.
Martella, G., Madeo, G., Maltese, M., Vanni, V., Puglisi, F., Ferraro, E., et al. (2016). Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice. NEUROBIOLOGY OF DISEASE, 91, 21-36 [10.1016/j.nbd.2015.12.020].
|Tipologia:||Articolo su rivista|
|Citazione:||Martella, G., Madeo, G., Maltese, M., Vanni, V., Puglisi, F., Ferraro, E., et al. (2016). Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice. NEUROBIOLOGY OF DISEASE, 91, 21-36 [10.1016/j.nbd.2015.12.020].|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.nbd.2015.12.020|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||23-feb-2016|
|Titolo:||Exposure to low-dose rotenone precipitates synaptic plasticity alterations in PINK1 heterozygous knockout mice|
|Autori:||Martella, G; Madeo, G; Maltese, M; Vanni, V; Puglisi, F; Ferraro, E; Schirinzi, T; Valente, EM; Bonanni, L; Shen, J; Mandolesi, G; Mercuri, NB; Bonsi, P; Pisani, A|
|Appare nelle tipologie:||01 - Articolo su rivista|