TY - JOUR T1 - Deletion of Tsc2 in Nociceptors Reduces Target Innervation, Ion Channel Expression and Sensitivity to Heat JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0436-17.2018 SP - ENEURO.0436-17.2018 AU - Dan Carlin AU - Judith P. Golden AU - Amit Mogha AU - Vijay K. Samineni AU - Kelly R. Monk AU - Robert W. Gereau IV AU - Valeria Cavalli Y1 - 2018/04/25 UR - http://www.eneuro.org/content/early/2018/04/25/ENEURO.0436-17.2018.abstract N2 - 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 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.Significance Statement mTORC1 activation promotes regeneration of injured peripheral axons, however it may have a negative effect on target innervation as well as alter normal sensory function and injury-induced pain. Acute and chronic mTORC1 inhibition may have different effects on sensory behavior. For the mTORC1 pathway to be considered as a therapeutic target to promote nerve regeneration, it is necessary to gain an understanding of the effects of chronic pathway activation on nociceptors and sensory behavior. We show that constitutive mTORC1 activation in nociceptors via conditional deletion of its negative regulator Tsc2 results in anomalies in cell morphology and gene expression that may underlie the decrease in noxious heat sensitivity and the attenuated nerve injury-induced cold hypersensitivity observed in Tsc2-deleted mice. ER -