Unraveling the role of satellite glial cells in sensory hypersensitivity in Fragile X syndrome

摘要 脆性X综合征（FXS）是自闭症谱系障碍（ASD）的主要已知遗传原因。一些 FXS和ASD最普遍的症状是躯体感觉缺陷和对感觉的超敏反应。 刺激。越来越多的证据表明，感觉超敏导致行为改变，如 眼神交流不佳焦虑社交障碍迄今为止，FXS中的感觉超敏反应一直是 这主要归因于大脑回路中的感觉处理缺陷。然而，尽管20年的密集 研究，FXS中感觉缺陷的机制仍然知之甚少，没有针对性的治疗方法， available.背根神经节（DRG）中的外周感觉神经元接受来自 并将其传递到中枢神经系统。感觉神经元的活动受卫星的调节 神经胶质细胞（SGCs），其完全包裹每个感觉神经元索马以形成形态学和 功能单元SGC-神经元通信是双向的，并且提供神经元通信的反馈控制。 活动已知SCG-神经元通信的失调有助于神经元的过度兴奋， 许多疼痛综合征。然而，在FXS中，SGC-神经元通信是否被破坏以及在多大程度上被破坏， SGCs对FXS中感觉缺陷的贡献仍然知之甚少。为了应对这一挑战，我们 开始探索FXS小鼠模型Fmr 1 KO小鼠中SGC-神经元通讯的潜在缺陷。 我们发现，感觉神经元表现出明显的超兴奋性在Fmr 1基因敲除小鼠。我们的发现与 最近对其他ASD模型的研究表明，核心认知和感觉缺陷可能源于 感觉输入的早期异常，导致随后皮层回路的异常发展。在 除了内在神经元机制的异常，我们发现感觉神经元的关联 神经元及其包裹的SGCs被破坏。此外，神经元和 SGCs指示参与SGCs-神经元通信的通路的失调。我们将研究是否和 神经元和SGCs之间的双向信号传导如何在Fmr 1 KO中被破坏。为实现这些目标将 神经元-SGC通信中谷氨酸和ATP释放的可视化和分析。我们将进一步 使用质谱方法确定SGC分泌的蛋白质以及SGC中的变化 FMRP缺失引起的分泌蛋白。最后，我们将评估靶向神经元-SGCs的通讯是否得到改善 神经元的兴奋性，并作为一个证明的原则，可以正常化的一个子集的相关行为缺陷，在 FXS小鼠模型。我们还将生成SGC特异性Fmr 1 KO，以确定SGC中的哪些缺陷。 神经元通信是由SGCs中FMRP的丢失引起的。我们的研究将提供基础 以确定SGC神经元通信的缺陷以及它们如何导致感觉超敏反应， FXS，有可能开辟新的方向，以改善FXS的感觉缺陷。

ABSTRACT Fragile X syndrome (FXS) is the leading known genetic cause of autism spectrum disorders (ASD). Some of the most prevalent symptoms of FXS and ASD are somatosensory deficits and hypersensitivity to sensory stimuli. Increasing evidence suggests that sensory hypersensitivity leads to behavioral alterations such as poor eye contact, anxiety, and impaired social interactions. Sensory hypersensitivity in FXS has thus far been largely attributed to sensory processing deficits in brain circuits. Yet, despite two decades of intensive studies, mechanisms of sensory deficits in FXS remain poorly understood and no targeted treatments are available. Peripheral sensory neurons in dorsal root ganglia (DRG) receive direct sensory information from the skin and convey it to the central nervous system. Activity of sensory neurons is modulated by satellite glial cells (SGCs), which completely envelop each sensory neuron soma to form a morphological and functional unit. SGC-neuron communication is bi-directional and provides feed-back control of neuronal activity. Dysregulation of SCG-neuron communication is known to contribute to neuronal hyperexcitability in many pain syndromes. Yet, whether SGC-neuron communication is disrupted in FXS and to what extent SGCs contribute to sensory deficits in FXS remains poorly understood. In response to this challenge, we began to explore potential deficits in SGC-neuron communication in Fmr1 KO mice, the FXS mouse model. We found that sensory neurons exhibit pronounced hyperexcitability in Fmr1 KO mice. Our findings are in line with recent studies in other models of ASD suggesting that core cognitive and sensory deficits may arise from an earlier abnormality in sensory inputs that drive subsequent abnormal development of cortical circuits. In addition to abnormalities in intrinsic neuronal mechanisms, we discovered that association of sensory neurons with their enveloping SGCs is disrupted. Furthermore, transcriptional changes in both neurons and SGCs indicate dysregulation of pathways involved in SGC-neuron communication. We will examine if and how bi-directional signaling between neurons and SGCs is disrupted in Fmr1 KO. This will be achieved by visualization and analysis of glutamate and ATP release in neuron-SGC communication. We will further define the proteins secreted by SGC using mass spectrometry approaches and the changes in the SGC secretome caused by FMRP loss. Finally, we will assess if targeting neuron-SGCs communication improves neuronal excitability and, as a proof-of-principle, can normalize a subset of relevant behavioral deficits in the FXS mouse model. We will also generate an SGC-specific Fmr1 KO to determine which defects in SGC- neuron communication are specifically caused by loss of FMRP in SGCs. Our studies will provide foundation to define the defects in SGC-neuron communication and how they contribute to sensory hypersensitivity in FXS, with a potential to open new directions to ameliorate sensory deficits in FXS.