analysis of abnormal neuronal excitability mediated by alpha-synuclein oligomer

我们利用全细胞膜片移液器将蛋白注射到小鼠皮层锥体神经元中，研究α -突触核蛋白寡聚物对神经元兴奋性的作用。Western blot分析显示，α -突触核蛋白与多巴胺（aS+DA）孵育的移液液中含有高阶低聚物。细胞内应用aS+DA抑制电流注射时的尖峰放电。尼莫地平和阿帕胺阻断了aS+DA对大鼠spike放电的影响。在电流箝位下，aS+DA延长了超极化后的峰值持续时间，增加了AHP过程中电流携带的电荷转移，这两种作用均被apamin抑制。这些结果表明α -突触核蛋白寡聚物通过增强AHP抑制峰值频率，而阿帕胺敏感的sk型钙活化钾通道参与了这种增强。这一机制可能导致帕金森病和伴路易体痴呆的新皮质活动下调。

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.