Objective: To investigate the effects of the exposure to low-dose rotenone of heterozygous PINK1 knockout (PINK1+/-) mice, compared to their wild-type littermates (PINK1+/+), on dopamine-dependent striatal synaptic plasticity, in the absence of apparent structural alterations.

Background: Heterozygous mutations in the PINK1 gene are considered a susceptibility factor to develop early-onset Parkinson’s disease, as supported by dopamine hypometabolism in asymptomatic mutation carriers and subtle alterations of striatal synaptic plasticity in PINK1+/- mice. Thus, the heterozygous condition offers the opportunity to examine the combination of an inherited susceptibility with environmental factors, such as pesticide exposure.

Methods: Mice were chronically treated with low-doses of rotenone (0.01-1mg/Kg). Immunofluorescence experiments on striatal slices of rotenone-treated mice were performed to assess the localization of two mitochondrial proteins, Tom20 and Cytochrome C. Moreover, we measured ATP content in mesencephalic and striatal slices by ATP bioluminescence assay. Electrophysiological recordings of striatal medium spiny neurons (MSNs) were performed through conventional sharp and patch-clamp techniques.

Results: Chronic rotenone (up to 0.8mg/Kg) treatment did not cause neuronal loss or changes in ATP levels both in the striatum and substantia nigra of PINK1+/- and PINK1+/+ mice, and did not induce mislocalization of Tom20 and release of Cytochrome C in PINK1+/- striatum. Basic electrophysiological properties of MSNs and nigral dopaminergic neurons were normal, whereas a complete loss of both Long-Term Depression (LTD) and Long-Term Potentiation (LTP) was recorded in MSNs from PINK1+/- mice. Interestingly, a preventive treatment with the antioxidant agent Trolox rescued synaptic plasticity impairment, confirming that, at these doses, rotenone did not induce irreversible alterations.

Conclusions: Our data suggest that chronic exposure to low-dose rotenone is not sufficient to alter mitochondrial integrity and ATP production, but profoundly impairs the expression of long-term plasticity at corticostriatal synapses in PINK1+/- mice, suggesting that disruption of synaptic plasticity may represent an early hallmark of a pre-clinical condition and a potential tool to test novel neuroprotective agents.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mild-mitochondrial-impairment-promotes-corticostriatal-synaptic-plasticity-alterations-in-pink1-heterozygous-knockout-mice/