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。一些人 FXS和ASD最常见的症状是躯体感觉障碍和感觉过敏 刺激物。越来越多的证据表明，感觉过敏会导致行为变化，如 眼神交流不畅、焦虑和社交能力受损。到目前为止，FXS的感觉超敏反应 这在很大程度上归因于大脑回路中的感觉处理缺陷。然而，尽管经过了20年的密集 研究表明，FXS感觉障碍的机制仍然知之甚少，也没有有针对性的治疗方法 可用。背根神经节(DRG)的外周感觉神经元直接接受来自 皮肤，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 胶质细胞(SGCs)，它完全包裹每个感觉神经元胞体，形成一个形态和 功能单元。SGC-神经元通讯是双向的，并提供神经元的反馈控制 活动。已知SCG-神经元通讯失调导致神经元过度兴奋性。 很多疼痛综合症。然而，在FXS中，SGC-神经元通讯是否中断，以及中断的程度如何 SGC在FXS中导致感觉缺陷的原因仍然知之甚少。为了应对这一挑战，我们 开始在FXS小鼠模型Fmr1 KO小鼠中探索SGC-神经元通信的潜在缺陷。 我们发现Fmr1KO小鼠的感觉神经元表现出明显的超兴奋性。我们的发现是一致的 最近对ASD其他模型的研究表明，核心认知和感觉缺陷可能源于 感觉输入的早期异常，导致随后皮质回路的异常发展。在……里面 除了内在神经机制的异常外，我们发现感觉的联系 神经元及其包裹的SGCs被破坏。此外，神经元和神经元的转录变化 SGCs提示参与SGC-神经元通讯的通路失调。我们将研究是否和 Fmr1KO中神经元和SGCs之间的双向信号是如何被破坏的。这将通过以下方式实现 神经元-SGC通讯中谷氨酸和ATP释放的可视化和分析。我们将进一步 用质谱学方法确定SGC分泌的蛋白质和SGC中的变化 FMRP缺失引起的分泌体。最后，我们将评估靶向神经元-SGCs的通讯是否有所改善 神经元兴奋性，作为一项原则证明，可以使脑内相关行为缺陷的子集正常化。 FXS小鼠模型。我们还将生成特定于SGC的Fmr1 KO，以确定SGC中的哪些缺陷- 神经元之间的通讯是由SGCs中FMRP的缺失引起的。我们的研究将为我们提供基础 为了明确SGC-神经元通讯中的缺陷及其对感觉超敏反应的影响 FXS，有可能开辟新的方向来改善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.