Striatal molecular signature of subchronic subthalamic nucleus high frequency stimulation in parkinsonian rat

Striatal gene expression profile was assessed in rats with nigral DOPAmine neuron lesion, either treated or not, using agilent microarrays and qPCR verification. The treatments consisted in anti-akinetic STN-HFS (5 days), chronic L-DOPA treatment inducing dyskinesia (LIDs) or the combination of the two treatments that exacerbated LIDs. STN-HFS modulated 71 genes with functional or biochemical annotation, including genes sharing the GO terms regulation of growth, regulation of apoptosis, extracellular region. Ttr, Igf2, Sostdc1 and Nr4A3 (Nor-1), are among the 5 genes showing the highest specific upregulation. Down-regulated genes include Prkcd, Sirt5 and Bbc3. These results show that genes involved in neuroprotection and/or neurogenesis are key components of STN-HFS action in the striatum. STN-HFS and LDOPA treatment share very few common gene regulation features suggesting that the molecular substrates underlying their striatal action are mostly different. In addition to genes already reported to be associated with LIDs (Pdyn, Trh, Grm4/mGlu4, Cnr1/CB1), the comparison between DOPA and DOPA/STN-HFS identifies immunity-related genes: C1s, Rt1-Da and Irf7a, as potential players in L-DOPA side effects.本研究针对黑质多巴胺能神经元损伤大鼠，采用安捷伦微阵列（Agilent Microarrays）技术开展纹状体基因表达谱分析，并通过qPCR（定量聚合酶链反应）进行验证。所涉治疗方案包括：持续5天的抗运动不能型丘脑底核高频电刺激（STN-HFS）、可诱发异动症（LIDs，即左旋多巴诱导性异动症）的慢性左旋多巴（L-DOPA）治疗，以及可加重异动症的两种治疗联合方案。STN-HFS可调控71个具备功能或生化注释的基因，其中涵盖符合生长调控、细胞凋亡调控及细胞外区域等基因本体（Gene Ontology, GO）术语的基因。Ttr、Igf2、Sostdc1与Nr4A3（Nor-1）属于上调幅度最高的5个特异性基因。下调基因则包括Prkcd、Sirt5及Bbc3。上述结果证实，参与神经保护和/或神经发生的基因是纹状体中STN-HFS发挥作用的关键核心组分。STN-HFS与L-DOPA治疗共有的基因调控特征极少，提示二者在纹状体中产生作用的分子基础大多存在差异。除已被报道与LIDs相关的基因（Pdyn、Trh、Grm4/mGlu4、Cnr1/CB1）外，对比单独L-DOPA治疗与L-DOPA联合STN-HFS治疗的样本，可发现免疫相关基因C1s、Rt1-Da及Irf7a可能是L-DOPA不良反应的潜在介导因子。