Deletion of Tsc2 in Nociceptors Reduces Target Innervation, Ion Channel Expression, and Sensitivity to Heat

Area of Science:

• Neuroscience
• Cellular Biology
• Pain Research

Background:

• Mechanistic target of rapamycin complex 1 (mTORC1) regulates cellular growth and is implicated in nerve regeneration.
• While mTORC1 activation can enhance axon growth, excessive signaling may cause innervation defects and pain hypersensitivity.
• The precise impact of mTORC1 activation on nociceptor phenotypes and sensory behaviors remains largely uncharacterized.

Purpose of the Study:

• To investigate the consequences of genetically activating mTORC1 in mouse peripheral sensory neurons.
• To determine the effects of excess mTORC1 signaling on nociceptor morphology, gene expression, and sensory function.

Main Methods:

• Genetic activation of mTORC1 in peripheral sensory neurons via conditional deletion of Tuberous Sclerosis Complex 2 (Tsc2) in mice.
• Analysis of C-nociceptor soma size and axon diameter.
• Fluorescence-associated cell sorting (FACS) for nociceptor enrichment and subsequent transcriptional profiling.
• Assessment of sensory behaviors, including sensitivity to heat, cold, and mechanical stimuli.

Main Results:

• Conditional deletion of Tsc2 led to increased soma size and axon diameter of C-nociceptors, consistent with mTORC1's role in cell growth.
• Disrupted innervation of glabrous skin and spinal cord by C-fiber neurons was observed.
• Transcriptional profiling revealed downregulation of ion channels and reduced expression of peptidergic nociceptor markers.
• Tsc2-deleted mice showed reduced sensitivity to noxious heat and decreased cold hypersensitivity after injury, but normal baseline cold and mechanical sensitivity.

Conclusions:

• Excessive mTORC1 activity in sensory neurons significantly alters gene expression and neuron morphology.
• Hyperactivation of mTORC1 impacts sensory neuron innervation and function.
• These findings demonstrate that dysregulated mTORC1 signaling in sensory neurons affects pain perception and neuronal characteristics.