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 Inhba, 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.

左旋多巴诱发的运动障碍 (LID) 是用左旋多巴进行慢性多巴胺 (DA) 替代疗法治疗帕金森病时引起的一种使人衰弱的运动副作用。 LID 与纹状体多巴胺能信号的超敏感性以及每次左旋多巴剂量后突触 DA 的波动有关，从而缩小了治疗窗口。纹状体的异质组成，包括中型多棘输出神经元 (MSN)、中间神经元和支持细胞的亚群，使 LID 潜在细胞的识别变得复杂。我们使用单核 RNA 测序 (snRNA-seq) 在 LID 发育过程中建立了全面的纹状体转录谱。雄性偏侧帕金森病小鼠用媒介物或左旋多巴治疗 1、5 或 10 天，并对纹状体核进行 snRNA-seq 处理。分析表明，有限数量的表达 DA D1 受体的 MSN (D1-MSN) 形成了三个亚簇，以响应 l-DOPA 治疗并表达细胞激活标记物。这些激活的 D1-MSN 显示出与之前与 LID 相关的类似转录变化；然而，它们的患病率和转录行为受到左旋多巴经验的不同影响。差异表达的基因表明可塑性相关转录因子和丝裂原激活蛋白激酶信号传导急剧上调，同时重复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) 信号传导基因。值得注意的是，在激活的 D1-MSN 中，重复的左旋​​多巴 (L-DOPA) 使 Inhba（TGF-β 超家族的激活素亚基）敏感，其药理抑制作用会损害 LID 的发展，表明激活素信号传导可能在 LID 中发挥重要作用。 这些数据表明，由于神经元夹带所需的分子机制的异常诱导，D1-MSN 的不同子集变得不同的左旋多巴反应，类似于海马学习和记忆的过程。