Universidad de Buenos Aires, CONICET, Instituto de Fisiología y Biofísica (IFIBIO) Bernardo Houssay, Grupo de Neurociencia de Sistemas, 2155 Paraguay Street, Buenos Aires, 1121, Argentina.
Departamento de Física Médica, Centro Atómico Bariloche and Instituto Balseiro, CONICET, 9500 Ezequiel Bustillo Avenue, San Carlos de Bariloche, Rio Negro, 8402, Argentina.
Mov Disord. 2021 Jul;36(7):1578-1591. doi: 10.1002/mds.28516. Epub 2021 Feb 6.
Enhanced striatal cholinergic interneuron activity contributes to the striatal hypercholinergic state in Parkinson's disease (PD) and to levodopa-induced dyskinesia. In severe PD, dyskinesia and motor fluctuations become seriously debilitating, and the therapeutic strategies become scarce. Given that the systemic administration of anticholinergics can exacerbate extrastriatal-related symptoms, targeting cholinergic interneurons is a promising therapeutic alternative. Therefore, unraveling the mechanisms causing pathological cholinergic interneuron activity in severe PD with motor fluctuations and dyskinesia may provide new molecular therapeutic targets.
We used ex vivo electrophysiological recordings combined with pharmacological and morphological studies to investigate the intrinsic alterations of cholinergic interneurons in the 6-hydroxydopamine mouse model of PD treated with levodopa.
Cholinergic interneurons exhibit pathological burst-pause activity in the parkinsonian "off levodopa" state. This is mediated by a persistent ligand-independent activity of dopamine D1/D5 receptor signaling, involving a cyclic adenosine monophosphate (cAMP) pathway. Dysregulation of membrane ion channels that results in increased inward-rectifier potassium type 2 (Kir2) and decreased leak currents causes the burst pause activity, which can be dampened by pharmacological inhibition of intracellular cAMP. A single challenge with a dyskinetogenic dose of levodopa is sufficient to induce persistent cholinergic interneuron burst-pause firing.
Our data unravel a mechanism causing aberrant cholinergic interneuron burst-pause activity in parkinsonian mice treated with levodopa. Targeting D5-cAMP signaling and the regulation of Kir2 and leak channels may alleviate parkinsonism and dyskinesia by restoring normal cholinergic interneuron function. © 2021 International Parkinson and Movement Disorder Society.
增强纹状体胆碱能中间神经元的活性会导致帕金森病（PD）中的纹状体乙酰胆碱过度活跃，并导致左旋多巴诱导的运动障碍。在严重的 PD 中，运动障碍和运动波动会变得非常虚弱，治疗策略变得稀缺。鉴于系统给予抗胆碱能药物会加重与纹状体无关的症状，因此针对胆碱能中间神经元是一种很有前途的治疗选择。因此，阐明导致伴有运动波动和运动障碍的严重 PD 中病理性胆碱能中间神经元活性的机制，可能为新的分子治疗靶点提供依据。
我们使用离体电生理记录结合药理学和形态学研究，来研究接受左旋多巴治疗的 6-羟多巴胺 PD 小鼠模型中胆碱能中间神经元的内在变化。
在帕金森病“停用左旋多巴”状态下，胆碱能中间神经元表现出病理性爆发暂停活动。这种活动是由多巴胺 D1/D5 受体信号的持续配体非依赖性活性介导的，涉及环磷酸腺苷（cAMP）途径。膜离子通道的失调导致内向整流钾型 2（Kir2）增加和漏电流减少，引起爆发暂停活动，通过细胞内 cAMP 的药理学抑制可以减轻这种活动。单次给予运动障碍剂量的左旋多巴足以诱导持续的胆碱能中间神经元爆发暂停放电。
我们的数据揭示了一种导致接受左旋多巴治疗的帕金森病小鼠中异常胆碱能中间神经元爆发暂停活动的机制。靶向 D5-cAMP 信号以及 Kir2 和漏通道的调节，可能通过恢复正常的胆碱能中间神经元功能来缓解帕金森病和运动障碍。© 2021 国际帕金森病和运动障碍学会。
