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

Washington University, Saint Louis MO

Investigators

Abstract

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.