Alpha-synuclein aggregates increase the conductance of substantia nigra dopamine neurons, an effect partly reversed by the KATP channel inhibitor glibenclamide
Dopaminergic neurons in the substantia nigra pars compacta (SNpc) form an important part of the basal ganglia circuitry, playing key roles in movement initiation and co-ordination. A hallmark of Parkinson’s disease (PD) is the degeneration of these SNpc dopaminergic neurons leading to akinesia, bradykinesia and tremor. There is gathering evidence that oligomeric alpha synuclein (α-syn) is one of the major pathological species in PD, with its deposition in Lewy bodies closely correlated with disease progression. However the precise mechanisms underlying the effects of oligomeric α-syn on dopaminergic neuron function have yet to be fully defined. Here we have combined electrophysiological recording and detailed analysis to characterise the time-dependent effects of α-syn aggregates (consisting of oligomers and possibly small fibrils) on the properties of SNpc dopaminergic neurons. The introduction of α-syn aggregates into single dopaminergic neurons 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 minutes of dialysis but did not occur with the monomeric form of α-syn. The effects of α-syn aggregates could be significantly reduced by pre-incubation with the ATP-sensitive potassium channel (KATP) inhibitor glibenclamide. This data suggests that accumulation of α-syn aggregates in dopaminergic neurons may chronically activate KATP channels leading to a significant loss of excitability and dopamine release.
Significance statement Alpha synuclein oligomers are one of the key toxic species in Parkinson’s disease, with their accumulation leading to dopamine neuron dysfunction. Introducing alpha synuclein aggregates (oligomers and possibly small fibrils) into single substantia nigra dopamine neurons led to a marked increase in whole cell conductance and a corresponding fall in the firing rate. These changes were diminished by inhibiting ATP-sensitive K channels. Thus, the build-up of alpha synuclein oligomers during the progression of Parkinson’s disease could chronically shunt dopamine neurons, via channel activation (which may include KATP channel activation) to reduce dopamine release.