PDF(Pubmed)
Abstract：
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.
摘要：
L-DOPA诱导的运动障碍(LID)是由用于治疗帕金森病的L-DOPA的慢性多巴胺(DA)替代疗法引起的使人衰弱的运动副作用。LID与纹状体多巴胺能信号的超敏反应和每个L-DOPA剂量后突触DA的波动相关，缩小治疗窗口。纹状体的异质组成，包括中刺输出神经元（MSN）的亚群，中间神经元，和支持细胞，使LID底层单元的识别复杂化。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。用媒介物或L-DOPA处理雄性h失模小鼠1、5或10天，并处理纹状体核进行snRNA-seq。分析表明，表达DAD1受体的MSN（D1-MSN）的有限群体响应L-DOPA处理形成了三个亚簇，并表达了激活的细胞标志物。这些激活的D1-MSN显示类似的转录变化，以前与LID相关；然而，他们的患病率和转录行为受到L-DOPA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，而反复的L-DOPA诱导突触重塑，学习和记忆，和转化生长因子β（TGF-β）信号基因。值得注意的是,重复L-DOPA致敏Inhba，TGF-β超家族的活化素亚基，在激活的D1-MSNs及其药理抑制作用中，LID发育受损，这表明激活素信号可能在LID中起重要作用。这些数据表明，由于神经元夹带所必需的分子机制的异常诱导，D1-MSN的不同子集变得差异L-DOPA反应，类似于海马学习和记忆的过程。意义陈述这些数据在帕金森病小鼠模型中的单个细胞水平上建立了跨L-DOPA诱导的运动障碍发展的纹状体的全面转录谱，表明纹状体神经元的独特亚簇对L-DOPA的经验有差异。这些神经元具有丰富的突触可塑性标记，学习和记忆背后的神经元夹带，和激活素信号。激活素受体的负调节抑制了L-DOPA诱导的运动障碍的发展，表明激活素直接调节对慢性L-DOPA的异常行为敏化。
