The dorsal root ganglia (DRG) are a diverse collection of sensory neurons that convey information such as proprioception, mechanosensation and temperature from the periphery to the CNS. Stimuli that activate specific DRG neurons (nociceptors) can trigger pain sensation. There is increasing evidence that satellite glial cells (SGCs), which surround the DRG neurons, modulate sensory processing, particularly for chronic pain. The overall objective of this project is to elucidate the mechanisms by which SGCs influence sensory neuron function; particularly, how the engulfment receptor Jedi1, expressed by SGCs, regulates nociceptive neurons. SGCs form a tight barrier around DRG neurons and buffer the local milieu, thereby regulating neuronal activity. In addition, we demonstrated that SGCs are the primary phagocytes that clear apoptotic neurons during development of the DRG and identified Jedi1 as a novel engulfment receptor expressed by these glia. To investigate the in vivo role of Jedi1, we generated jedi1-/- mice. In the DRG from null mice the removal of dead cells during development was impaired. Interestingly, despite Jedi1 expression only being detected in the glia and not the neurons, we found altered function of jedi1-/- sensory neurons. Electrical recording from perinatal jedi1-/- DRG neurons revealed a substantial increase in excitability; most wild type neurons only fired 1-2 action potentials in response to current injection, whereas most jedi-/- cells fired multiple action potentials. Such enhanced excitability is typical of DRG neurons in early development and following nerve injury. The hypersensitivity was accompanied by a 25% decrease in the number of DRG neurons in adult, but not perinatal jedi1-/- mice, suggesting there may be excitotoxic neurodegeneration. In addition, there was a 30% increase in the fraction of DRG neurons responsive to capsaicin, which was paralleled by enhanced capsaicin-induced allodynia in jedi1-/- mice relative to wild type. Enhanced excitability, a greater fraction of capsaicin responsive neurons and increased susceptibility to apoptosis, are all associated with DRG neurons in early development, suggesting defects in the normal maturation of jedi1-/- neurons. Therefore, we hypothesize that loss of Jedi1 in SGCs results in impaired sensory neuron maturation, which leads to altered nociception and excitotoxic neurodegeneration. To test this hypothesis, we will (1) determine which sensory modalities are altered in jedi1-/- mice, (2) determine if loss of Jedi1 selectively in SGCs during development leads to an altered sensory neuron phenotype, (3) identify the mechanism underlying the sensory neuron phenotype. These studies will reveal fundamental mechanisms by which glia regulate neuronal function and sensory perception, provide a foundation for understanding how dysfunctional signaling can lead to peripheral sensitization and disease, and potentially identify novel targets for the treatment of chronic pain.
There is increasing evidence that peripheral glial cells regulate sensory neuron activity and contribute to the development of chronic pain. We identified Jedi1 as a novel receptor expressed by peripheral glial cells involved in the removal of dead neurons that normally accumulate during development. Mice lacking Jedi1 exhibit an increase in specific types of pain-sensing neurons, enhanced sensitivity to painful stimuli and neurodegeneration; therefore, we propose to determine the mechanism by which loss of Jedi1 alters the communication between glia and neurons, leading to these phenotypes.
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