Deletion of Tsc2 in Nociceptors Reduces Target Innervation, Ion Channel Expression, and Sensitivity to Heat.
Deletion of Tsc2 in Nociceptors Reduces Target Innervation, Ion Channel Expression, and Sensitivity to Heat.
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DOI：
10.1523/eneuro.0436-17.2018
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发表时间：
2018-03
期刊：
影响因子：
3.4
通讯作者：
Cavalli V
中科院分区：
文献类型：
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作者：
Carlin D;Golden JP;Mogha A;Samineni VK;Monk KR;Gereau RW 4th;Cavalli V
已知雷帕霉素复合物1（mTORC 1）的机制靶点调节细胞生长途径，并且其遗传激活足以增强中枢或外周神经系统损伤后的再生轴突生长。然而，过量的mTORC 1激活可能促进神经支配缺陷，并且mTORC 1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热情。虽然mTORC 1活性是完全表达某些疼痛模式所必需的，但通路激活对伤害感受器表型和感觉行为的影响目前尚不清楚。为了解决这一问题，我们在小鼠外周感觉神经元中通过有条件地删除其负调节因子肥大性硬化症复合物2（Tsc 2）来遗传激活mTORC 1。与众所周知的mTORC 1在调节细胞大小中的作用一致，在Tsc 2缺失的小鼠中，C-伤害感受器的索马大小和轴突直径增加。光滑的皮肤和C-纤维神经元的脊髓神经支配也被破坏。通过荧光相关细胞分选（FACS）富集的伤害感受器的转录谱显示多种类型的离子通道的下调以及Tsc 2缺失小鼠中肽能伤害感受器的标记物的表达减少。除了神经支配和基因表达的这些变化，Tsc 2缺失小鼠表现出降低的伤害性热敏感性和降低的损伤诱导的冷敏感性，但对冷和机械刺激的基线敏感性正常。总之，这些数据表明，感觉神经元中过量的mTORC 1活性会引起基因表达、神经元形态和感觉行为的变化。
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.