Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294.
J Neurosci. 2024 Jun 26;44(26):e0050242024. doi: 10.1523/JNEUROSCI.0050-24.2024.
l-DOPA-induced dyskinesia (LID) is a debilitating motor side effect arising from chronic dopamine (DA) replacement therapy with l-DOPA for the treatment of Parkinson's disease. LID is associated with supersensitivity of striatal dopaminergic signaling and fluctuations in synaptic DA following each l-DOPA dose, shrinking the therapeutic window. The heterogeneous composition of the striatum, including subpopulations of medium spiny output neurons (MSNs), interneurons, and supporting cells, complicates the identification of cell(s) underlying LID. We used single-nucleus RNA sequencing (snRNA-seq) to establish a comprehensive striatal transcriptional profile during LID development. Male hemiparkinsonian mice were treated with vehicle or l-DOPA for 1, 5, or 10 d, and striatal nuclei were processed for snRNA-seq. Analyses indicated a limited population of DA D1 receptor-expressing MSNs (D1-MSNs) formed three subclusters in response to l-DOPA treatment and expressed cellular markers of activation. These activated D1-MSNs display similar transcriptional changes previously associated with LID; however, their prevalence and transcriptional behavior were differentially influenced by l-DOPA experience. Differentially expressed genes indicated acute upregulation of plasticity-related transcription factors and mitogen-activated protein kinase signaling, while repeated l-DOPA-induced synaptic remodeling, learning and memory, and transforming growth factor-β (TGF-β) signaling genes. Notably, repeated l-DOPA sensitized , an activin subunit of the TGF-β superfamily, in activated D1-MSNs, and its pharmacological inhibition impaired LID development, suggesting that activin signaling may play an essential role in LID. These data suggest distinct subsets of D1-MSNs become differentially l-DOPA-responsive due to aberrant induction of molecular mechanisms necessary for neuronal entrainment, similar to processes underlying hippocampal learning and memory.
左旋多巴诱导的运动障碍（LID）是一种进行性的运动副作用，它源于慢性多巴胺（DA）替代疗法，用左旋多巴治疗帕金森病。LID 与纹状体多巴胺能信号的超敏性以及每次左旋多巴剂量后的突触 DA 波动有关，缩小了治疗窗口。纹状体的异质性组成，包括中间神经元和支持细胞的中脑输出神经元（MSNs）亚群，使得确定 LID 潜在的细胞变得复杂。我们使用单细胞 RNA 测序（snRNA-seq）在 LID 发展过程中建立了一个全面的纹状体现转录谱。雄性半帕金森病小鼠用载体或左旋多巴治疗 1、5 或 10 天，然后处理纹状体核进行 snRNA-seq。分析表明，对左旋多巴治疗有反应的 DA D1 受体表达的 MSNs（D1-MSNs）形成了三个亚群，并表达了激活的细胞标记物。这些激活的 D1-MSNs 表现出与 LID 先前相关的相似转录变化；然而，它们的流行程度和转录行为受到左旋多巴经验的不同影响。差异表达基因表明，可塑性相关转录因子和丝裂原活化蛋白激酶信号的急性上调，而重复的左旋多巴诱导的突触重塑、学习和记忆以及转化生长因子-β（TGF-β）信号基因。值得注意的是，重复的左旋多巴使 TGF-β超家族的激活素亚单位在激活的 D1-MSNs 中变得敏感，其药理学抑制作用损害了 LID 的发展，表明激活素信号可能在 LID 中发挥重要作用。这些数据表明，由于诱导神经元同步所需的分子机制异常，D1-MSNs 的不同亚群变得对左旋多巴反应不同，类似于海马学习和记忆背后的过程。
