Abstract
In a preceding study, we showed that in adult pink1−/− mice, a monogenic animal model of Parkinson’s disease (PD), striatal neurons display aberrant electrical activities that precede the onset of overt clinical manifestations. Here, we tested the hypothesis that the maturation of dopaminergic (DA) neurons of the pink1−/− substantia nigra compacta (SNc) follows, from early stages on, a different developmental trajectory from age-matched wild type (wt) SNc DA neurons. We used immature (postnatal days P2–P10) and young adult (P30–P90) midbrain slices of pink1−/− mice expressing the green fluorescent protein in tyrosine hydroxylase (TH)-positive neurons. We report that the developmental sequence of N-Methyl-D-aspartic acid (NMDA) spontaneous excitatory postsynaptic currents (sEPSCs) is altered in pink1−/− SNc DA neurons, starting from shortly after birth. They lack the transient episode of high NMDA receptor-mediated neuronal activity characteristic of the immature stage of wt SNc DA neurons. The maturation of the membrane resistance of pink1−/− SNc DA neurons is also altered. Collectively, these observations suggest that electrical manifestations occurring shortly after birth in SNc DA neurons might lead to dysfunction in dopamine release and constitute an early pathogenic mechanism of PD.
Highlights
Dopaminergic (DA) neurons of the substantia nigra compacta (SNc) degenerate progressively during the course of Parkinson’s disease (PD; Kordower et al, 2013)
The main result shown here is that pink1−/− SNc DA neurons lack the characteristic wt developmental sequence of N-Methyl-D-aspartic acid (NMDA) spontaneous excitatory postsynaptic currents (sEPSCs) identified between P2 and P10, which consists of large amplitude and high frequency events associated sEPSCs in Developing Pink1−/− Dopaminergic Neurons
To a characteristic bursting pattern. The absence of this high NMDA activity at immature stage drastically changes the developmental profile of NMDA sEPSCs in pink1−/− SNc DA neurons
Summary
Dopaminergic (DA) neurons of the substantia nigra compacta (SNc) degenerate progressively during the course of Parkinson’s disease (PD; Kordower et al, 2013) Whether and when they dysfunction during the early stages of PD before degenerating remains largely unknown. Pink is stabilized on the outer mitochondrial membrane, where it phosphorylates ubiquitin and activates the ubiquitin ligase parkin. This builds ubiquitin chains on mitochondrial outer membrane proteins and leads to removal of damaged mitochondria by autophagy (Narendra et al, 2010; Koyano et al, 2014; Kazlauskaite and Muqit, 2015; Lazarou et al, 2015; Ordureau et al, 2015)
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