Zhai Shenyu, Cui Qiaoling, Wokosin David, Sun Linqing, Tkatch Tatiana, Crittenden Jill R, Graybiel Ann M, Surmeier D James
Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815 USA.
bioRxiv. 2025 Jan 7:2025.01.02.631090. doi: 10.1101/2025.01.02.631090.
In the later stages of Parkinson's disease (PD), patients often manifest levodopa-induced dyskinesia (LID), compromising their quality of life. The pathophysiology underlying LID is poorly understood, and treatment options are limited. To move toward filling this treatment gap, the intrinsic and synaptic changes in striatal spiny projection neurons (SPNs) triggered by the sustained elevation of dopamine (DA) during dyskinesia were characterized using electrophysiological, pharmacological, molecular and behavioral approaches. Our studies revealed that the intrinsic excitability and functional corticostriatal connectivity of SPNs in dyskinetic mice oscillate between the on- and off-states of LID in a cell- and state-specific manner. Although triggered by levodopa, these rapid oscillations in SPN properties depended on both dopaminergic and cholinergic signaling. In a mouse PD model, disrupting M1 muscarinic receptor signaling specifically in iSPNs or deleting its downstream signaling partner CalDAG-GEFI blunted the levodopa-induced oscillation in functional connectivity, enhanced the beneficial effects of levodopa and attenuated LID severity.
在帕金森病（PD）的后期阶段，患者常出现左旋多巴诱导的异动症（LID），这损害了他们的生活质量。LID的病理生理学机制尚不清楚，治疗选择也有限。为了填补这一治疗空白，我们采用电生理、药理学、分子和行为学方法，对异动症期间多巴胺（DA）持续升高触发的纹状体棘状投射神经元（SPN）的内在和突触变化进行了表征。我们的研究表明，异动症小鼠中SPN的内在兴奋性和功能性皮质纹状体连接性以细胞和状态特异性的方式在LID的开启和关闭状态之间振荡。尽管这些SPN特性的快速振荡是由左旋多巴触发的，但它们依赖于多巴胺能和胆碱能信号传导。在小鼠PD模型中，特异性破坏iSPN中的M1毒蕈碱受体信号传导或删除其下游信号伴侣CalDAG-GEFI，可减弱左旋多巴诱导的功能连接振荡，增强左旋多巴的有益作用，并减轻LID的严重程度。
