Universidad de Buenos Aires, CONICET, Instituto de Fisiología y Biofísica (IFIBIO) Bernardo Houssay, Grupo de Neurociencia de Sistemas, Buenos Aires, Argentina.
Mov Disord. 2022 Aug;37(8):1693-1706. doi: 10.1002/mds.29055. Epub 2022 May 9.
In advanced stages of Parkinson's disease (PD), dyskinesia and motor fluctuations become seriously debilitating and therapeutic options become scarce. Aberrant activity of striatal cholinergic interneurons (SCIN) has been shown to be critical to PD and dyskinesia, but the systemic administration of cholinergic medications can exacerbate extrastriatal-related symptoms. Thus, targeting the mechanisms causing pathological SCIN activity in severe PD with motor fluctuations and dyskinesia is a promising therapeutic alternative.
We used ex vivo electrophysiological recordings combined with pharmacology to study the alterations in intracellular signaling that contribute to the altered SCIN physiology observed in the 6-hydroxydopamine mouse model of PD treated with levodopa.
The altered phenotypes of SCIN of parkinsonian mice during the "off levodopa" state resulting from aberrant Kir/leak and Kv1.3 currents can be rapidly reverted by acute inhibition of cAMP-ERK1/2 signaling. Inverse agonists that inhibit the ligand-independent activity of D5 receptors, like clozapine, restore Kv1.3 and Kir/leak currents and SCIN normal physiology in dyskinetic mice.
Our work unravels a signaling pathway involved in the dysregulation of membrane currents causing SCIN hyperexcitability and burst-pause activity in parkinsonian mice treated with levodopa (l-dopa). These changes persist during off-medication periods due to tonic mechanisms that can be acutely reversed by pharmacological interventions. Thus, targeting the D5-cAMP-ERK1/2 signaling pathway selectively in SCIN may have therapeutic effects in PD and dyskinesia by restoring the normal SCIN function. © 2022 International Parkinson and Movement Disorder Society.
在帕金森病（PD）的晚期，运动障碍和运动波动变得严重衰弱，治疗选择变得稀缺。纹状体胆碱能中间神经元（SCIN）的异常活动被证明对 PD 和运动障碍至关重要，但胆碱能药物的全身给药会加重与纹状体无关的症状。因此，针对伴有运动波动和运动障碍的严重 PD 中导致病理性 SCIN 活动的机制是一种有前途的治疗选择。
我们使用离体电生理记录结合药理学方法研究了导致接受左旋多巴治疗的 6-羟多巴胺 PD 小鼠模型中观察到的 SCIN 生理学改变的细胞内信号转导改变。
在“停用左旋多巴”状态下，帕金森病小鼠的 SCIN 表型发生改变，这是由于 Kir/渗漏和 Kv1.3 电流异常所致，这种改变可以通过快速抑制 cAMP-ERK1/2 信号转导而迅速逆转。抑制 D5 受体配体非依赖性活性的反向激动剂，如氯氮平，可恢复 Kv1.3 和 Kir/渗漏电流，并使运动障碍小鼠的 SCIN 恢复正常生理学。
我们的工作揭示了一种信号通路，该通路参与调节导致接受左旋多巴（l-dopa）治疗的帕金森病小鼠 SCIN 过度兴奋和爆发-停顿活动的膜电流失调。这些变化在停药期间持续存在，因为紧张机制可以通过药理学干预迅速逆转。因此，选择性地靶向 SCIN 中的 D5-cAMP-ERK1/2 信号通路可能通过恢复正常的 SCIN 功能对 PD 和运动障碍产生治疗作用。
