The role of the glial engulfment receptor Jedi1 in regulating sensory neuron function

背根神经节（DRG）是一个不同的感觉神经元的集合， 如本体感觉、机械感觉和从外周到中枢神经系统的温度。刺激激活 特定的DRG神经元（伤害感受器）可以触发痛觉。越来越多的证据表明， 围绕DRG神经元的神经干细胞（SGCs）调节感觉处理，特别是对于慢性疼痛。 本课题的总体目标是阐明SGCs影响感觉神经元的机制 功能;特别是SGCs表达的吞噬受体Jedi 1如何调节伤害性神经元。 SGCs在DRG神经元周围形成紧密屏障并缓冲局部环境，从而调节神经元活性。 此外，我们证明了SGCs是清除凋亡神经元的主要吞噬细胞， DRG的发展，并确定Jedi 1作为一种新的吞噬受体表达这些胶质细胞。到 为了研究Jedi 1在体内的作用，我们产生了Jedi 1-/-小鼠。在来自无效小鼠的DRG中， 发育过程中的细胞受损。有趣的是，尽管Jedi 1的表达只在神经胶质细胞中检测到， 而不是神经元，我们发现了jedi 1-/-感觉神经元的功能改变。围产期电记录 jedi 1-/- DRG神经元显示出兴奋性的显著增加;大多数野生型神经元仅激发1-2 动作电位响应电流注入，而大多数绝地-/-细胞发射多个动作电位。 这种增强的兴奋性是DRG神经元在早期发育和神经损伤后的典型特征。的 超敏反应伴随着成年人DRG神经元数量减少25%，但不伴随着围产期 jedi 1-/-小鼠，提示可能存在兴奋毒性神经变性。此外， DRG神经元对辣椒素反应的分数，这被增强的辣椒素诱导的 Jedi 1-/-小鼠相对于野生型的异常性疼痛。增强兴奋性，更大比例的辣椒素反应 神经元和增加的对凋亡的敏感性，都与早期发育中的DRG神经元有关， 提示JDI 1-/-神经元正常成熟中的缺陷。因此，我们假设失去绝地1 导致感觉神经元成熟受损，这导致伤害感受改变， 兴奋毒性神经变性为了验证这一假设，我们将（1）确定哪些感觉方式是 在jedi 1-/-小鼠中改变，（2）确定在发育过程中SGCs中选择性地丢失Jedi 1是否会导致 改变感觉神经元表型，（3）确定感觉神经元表型的机制。 这些研究将揭示胶质细胞调节神经元功能和感觉神经元功能的基本机制。 感知，为理解功能失调的信号传导如何导致外周 致敏和疾病，并可能确定新的目标，用于治疗慢性疼痛。

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.