analysis of abnormal neuronal excitability mediated by alpha-synuclein oligomer

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We examined the action of alpha-synuclein oligomers on neuronal excitabilities by injecting protein into pyramidal neurons in mouse cortical slices through whole-cell patch pipettes.Western blot analysis showed that the pipette solution including alpha-synuclein incubated with dopamine (aS+DA), had higher order oligomer. Intracellular application of aS+DA suppressed spike firing during current injection. Nimodipine and apamin blocked the effect of aS+DA on spike firing. aS+DA prolonged the duration of spike afterhyperpolarization (AHP) and increased the charge transfer carried by the current during AHP under current clamp, both of which were inhibited by apamin.These results suggest that alpha-synuclein oligomers suppress spike frequency by enhancing AHP, and apamin-sensitive SK-type calcium-activated potassium channel is involved with the enhancement. This mechanism may cause the downregulation of neocortical activities in Parkinson's disease and dementia with Lewy bodies.