Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110.
Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110.
eNeuro. 2018 May 3;5(2). doi: 10.1523/ENEURO.0436-17.2018. eCollection 2018 Mar-Apr.
The mechanistic target of rapamycin complex 1 (mTORC1) is known to regulate cellular growth pathways, and its genetic activation is sufficient to enhance regenerative axon growth following injury to the central or peripheral nervous systems. However, excess mTORC1 activation may promote innervation defects, and mTORC1 activity mediates injury-induced hypersensitivity, reducing enthusiasm for the pathway as a therapeutic target. While mTORC1 activity is required for full expression of some pain modalities, the effects of pathway activation on nociceptor phenotypes and sensory behaviors are currently unknown. To address this, we genetically activated mTORC1 in mouse peripheral sensory neurons by conditional deletion of its negative regulator Tuberous Sclerosis Complex 2 (Tsc2). Consistent with the well-known role of mTORC1 in regulating cell size, soma size and axon diameter of C-nociceptors were increased in Tsc2-deleted mice. Glabrous skin and spinal cord innervation by C-fiber neurons were also disrupted. Transcriptional profiling of nociceptors enriched by fluorescence-associated cell sorting (FACS) revealed downregulation of multiple classes of ion channels as well as reduced expression of markers for peptidergic nociceptors in Tsc2-deleted mice. In addition to these changes in innervation and gene expression, Tsc2-deleted mice exhibited reduced noxious heat sensitivity and decreased injury-induced cold hypersensitivity, but normal baseline sensitivity to cold and mechanical stimuli. Together, these data show that excess mTORC1 activity in sensory neurons produces changes in gene expression, neuron morphology and sensory behavior.
雷帕霉素靶蛋白复合物 1（mTORC1）的作用机制被认为可以调控细胞生长途径，其基因激活足以增强中枢或周围神经系统损伤后的再生轴突生长。然而，mTORC1 的过度激活可能会促进神经支配缺陷，并且 mTORC1 活性介导损伤诱导的超敏反应，降低了将该途径作为治疗靶点的积极性。虽然 mTORC1 活性对于某些疼痛模式的充分表达是必需的，但目前尚不清楚该途径的激活对伤害感受器表型和感觉行为的影响。为了解决这个问题，我们通过条件性删除其负调节剂结节性硬化复合物 2（Tsc2）在小鼠外周感觉神经元中基因激活 mTORC1。与 mTORC1 在调节细胞大小方面的作用一致，Tsc2 缺失小鼠的 C 伤害感受器的体大小和轴突直径增加。C 纤维神经元对无毛皮肤和脊髓的神经支配也被破坏。通过荧光激活细胞分选（FACS）富集伤害感受器的转录组分析显示，Tsc2 缺失小鼠中多种离子通道类别的下调以及肽能伤害感受器标志物的表达降低。除了这些神经支配和基因表达的变化外，Tsc2 缺失小鼠表现出对有害热刺激的敏感性降低和损伤诱导的冷超敏反应降低，但对冷和机械刺激的基线敏感性正常。综上所述，这些数据表明感觉神经元中过多的 mTORC1 活性会导致基因表达、神经元形态和感觉行为的变化。
