α-synuclein aggregates increase the conductance of substantia nigra dopamine neurons, an effect partly reversed by the KATP channel inhibitor glibenclamide

Abstract

Dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc) form an important part of the basal ganglia circuitry, playing key roles in movement initiation and coordination. A hallmark of Parkinson’s disease (PD) is the degeneration of these SNpc DNs leading to akinesia, bradykinesia and tremor. There is gathering evidence that oligomeric a-synuclein (a-syn) is one of the major pathologic species in PD, with its deposition in Lewy bodies (LBs) closely correlated with disease progression. However, the precise mechanismsunderlying the effects of oligomeric a-syn on DN function have yet to be fully defined. Here, we have combined electrophysiological recording and detailed analysis to characterize the time-dependent effects of a-syn aggregates (consisting of oligomers and possibly small fibrils) on the properties of SNpc DNs. The introduction of a-syn aggregates into single DNs via the patch electrode significantly reduced both the input resistance and the firing rate without changing the membrane potential. These effects occurred after 8-16 min of dialysis but did not occur with the monomeric form of a-syn. The effects of a-syn aggregates could be significantly reduced by preincubation with the ATP-sensitive K1 channel (KATP) inhibitor glibenclamide. These data suggest that accumulation of a-syn aggregates in DNs may chronically activate KATP channels leading to a significant loss of excitability and dopamine release.