Parkinson’s disease (PD) is clinically defined by the presence of the cardinal motor symptoms, which are associated with a loss of dopaminergic nigrostriatal neurons in the substantia nigra pars compacta (SNpc). While SNpc neurons serve as the prototypical cell-type to study cellular vulnerability in PD, there is an unmet need to extent our efforts to other neurons at risk. The noradrenergic locus coeruleus (LC) represents one of the first brain structures affected in Parkinson’s disease (PD) and plays not only a crucial role for the evolving non-motor symptomatology, but it is also believed to contribute to disease progression by efferent noradrenergic deficiency. Therefore, we sought to characterize the electrophysiological properties of LC neurons in two distinct PD models: (1) in an in vivo mouse model of focal α-synuclein overexpression; and (2) in an in vitro rotenone-induced PD model. Despite the fundamental differences of these two PD models, α-synuclein overexpression as well as rotenone exposure led to an accelerated autonomous pacemaker frequency of LC neurons, accompanied by severe alterations of the afterhyperpolarization amplitude. On the mechanistic side, we suggest that Ca²⁺-activated K⁺ (SK) channels are mediators of the increased LC neuronal excitability, as pharmacological activation of these channels is sufficient to prevent increased LC pacemaking and subsequent neuronal loss in the LC following in vitro rotenone exposure. These findings suggest a role of SK channels in PD by linking α-synuclein- and rotenone-induced changes in LC firing rate to SK channel dysfunction.

帕金森病 (PD) 的临床定义是存在主要运动症状，这些症状与黑质致密部 (SNpc) 中多巴胺能黑质纹状体神经元的丧失有关。虽然 SNpc 神经元作为原型细胞类型来研究 PD 中的细胞脆弱性，但仍有未满足的需要将我们的努力扩展到其他处于危险中的神经元。去甲肾上腺素能蓝斑 (LC) 是受帕金森病 (PD) 影响的第一个大脑结构之一，它不仅在不断发展的非运动症状学中起着至关重要的作用，而且还被认为有助于传出去甲肾上腺素能缺乏症的疾病进展. 因此，我们试图在两种不同的 PD 模型中表征 LC 神经元的电生理特性：（1）在局灶性 α-突触核蛋白过表达的体内小鼠模型中；(2) 在体外鱼藤酮诱导的 PD 模型中。尽管这两种 PD 模型存在根本差异，但 α-突触核蛋白过表达以及鱼藤酮暴露导致 LC 神经元的自主起搏器频率加速，伴随着后超极化幅度的严重改变。在机械方面，我们建议 Ca²⁺ -激活的 K ⁺ (SK) 通道是增加 LC 神经元兴奋性的介质，因为这些通道的药理学激活足以防止体外鱼藤酮暴露后 LC 起搏增加和随后的 LC 神经元损失。这些发现通过将 α-突触核蛋白和鱼藤酮诱导的 LC 放电率变化与 SK 通道功能障碍联系起来，表明 SK 通道在 PD 中的作用。