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

揭示卫星胶质细胞在脆性 X 综合征感觉超敏反应中的作用

基本信息

批准号：
10752180
负责人：
Valeria Cavalli
金额：
$ 42.76万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-06 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752180
关键词：
Acute Affect Afferent Neurons Anxiety Behavioral Brain Calcium Cell Communication Cell Culture System Cells Central Nervous System Cognitive Communication Defect Development Discrimination Dissociation Electrophysiology (science)Exhibits Eye FMR1 FMRP Feedback Foundations Fragile X Syndrome Genetic Genetic Transcription Glutamates Goals Hypersensitivity Imaging Device Impairment Kinetics Knockout Mice Link Mass Spectrum Analysis Measures Modeling Morphology Neuroglia Neuronal Dysfunction Neurons Pain Pathway interactions Perception Peripheral Process Protein Secretion Role Sensory Signal Transduction Skin Social Interaction Somatosensory Disorders Spinal Ganglia Symptoms Syndrome Technology Testing Texture Universities Validation Viral Visualization Washington autism spectrum disorder behavior test candidate selection cell type experimental study glutamatergic signaling high resolution imaging improved in vivo innovation mouse model neuronal cell body neuronal excitability neurotransmission neurotransmitter release response selective expression sensor sensory input sensory mechanism sensory stimulus tool

项目摘要

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.

抽象的脆性 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 最常见的症状是体感缺陷和感觉过敏刺激。越来越多的证据表明，感觉过敏会导致行为改变，例如目光接触不良、焦虑和社交互动受损。迄今为止，FXS 中的感觉超敏反应已被很大程度上归因于大脑回路的感觉处理缺陷。然而，尽管二十年来的密集研究表明，FXS 感觉缺陷的机制仍然知之甚少，并且没有针对性的治疗方法可用的。背根神经节 (DRG) 的外周感觉神经元接收直接感觉信息皮肤并将其传送到中枢神经系统。感觉神经元的活动由卫星调节神经胶质细胞（SGC），完全包裹每个感觉神经元胞体，形成形态和结构功能单元。 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-神经元通讯失调会导致神经元过度兴奋许多疼痛综合症。然而，FXS 中 SGC 与神经元的通讯是否受到干扰以及干扰程度如何？ SGC 导致 FXS 感觉缺陷的原因仍然知之甚少。为了应对这一挑战，我们开始探索 Fmr1 KO 小鼠（FXS 小鼠模型）中 SGC-神经元通讯的潜在缺陷。我们发现 Fmr1 KO 小鼠的感觉神经元表现出明显的过度兴奋。我们的发现是一致的最近对其他自闭症谱系障碍模型的研究表明，核心认知和感觉缺陷可能源于早期感觉输入异常，导致皮层回路随后异常发育。在除了内在神经元机制的异常之外，我们发现感觉的关联神经元及其包络的 SGC 被破坏。此外，神经元和 SGC 表明参与 SGC-神经元通讯的通路失调。我们将检查是否和 Fmr1 KO 中神经元和 SGC 之间的双向信号传导如何被破坏。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。我们将进一步使用质谱方法定义 SGC 分泌的蛋白质以及 SGC 的变化 FMRP 丢失导致的分泌蛋白组。最后，我们将评估靶向神经元-SGC 的通信是否得到改善神经元兴奋性，并且作为原理证明，可以使神经元中相关行为缺陷的子集正常化 FXS 鼠标型号。我们还将生成 SGC 特定的 Fmr1 KO 以确定 SGC 中的哪些缺陷神经元通讯特别是由 SGC 中 FMRP 的丢失引起的。我们的研究将为我们提供基础定义 SGC-神经元通讯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来改善 FXS 的感官缺陷。