Unraveling satellite glial cells dysfunctions in spiral ganglia of a mouse model of Fragile X syndrome

ABSTRACT Sensory neurons convey information about external and internal environment to the brain. Proper function of sensory neurons is regulated by different types of glial cells, and alterations in glial functions have emerged as a major contributing factor in many neurodevelopmental disorders. While Schwann cells

surrounding sensory axons are very well studied, much less is known about satellite glial cells (SGCs), which completely envelop sensory neuron soma in various sensory ganglia, including spiral ganglia mediating transduction of sound. Spiral ganglia neurons in the cochlea receive auditory information from hair cells in the

ear and convey it to the brain with high speed and precision. Small alterations in conduction velocity in these neurons have major effects on signal processing in the auditory circuits. Whether this peripheral auditory system is dysregulated by FMRP loss remains largely unknown. Sensory deficits, and particularly

hypersensitivity to sound is one of the hallmarks of Fragile X syndrome (FXS) and other autism-spectrum disorders. Increasing evidence suggests that sensory hypersensitivity in FXS leads to behavioral alterations such as anxiety and impaired social interactions. The defects have been thus far largely attributed to sensory

processing abnormalities in brain circuits. However, core sensory and cognitive deficits may arise from an earlier abnormality in sensory inputs that drive subsequent abnormal development of cortical circuits. Yet, the mechanisms of sensory deficits in FXS remain poorly understood and no targeted treatments are available. In

response to this challenge, we began to define potential deficits in spiral ganglia neurons in Fmr1 KO mice, the FXS mouse model. At the ultrastructural level, we observed altered association of spiral ganglia neurons with their enveloping SGCs. We found that genes related to neural development and myelination are

dysregulated in Fmr1 KO spiral ganglia. We also observed abnormal number of immune cells in Fmr1 KO spiral ganglia. Our initial observations point to potential deficits in the peripheral auditory system in FXS. The goal of this proposal is thus to unravel the contribution of SGCs to sensory hypersensitivity caused by FMRP

loss. To achieve this goal, we will first determine if and how cell type proportions and the transcriptome of cells in spiral ganglia are affected by loss of FMRP using single-cell RNAseq approaches at two critical developmental stages, postnatal day 5 (P5, pre-hearing), P15 (post-hearing), and P28. We will also perform

electron microscopy analyses of spiral ganglia at the same stages to define the developmental timeline by which SGCs envelop and myelinate spiral ganglia neuron soma in normal conditions and to identify when abnormalities caused by FMRP loss arise during development. Finally, we will determine if absence of FMRP

causes alterations in the excitability of auditory neurons. These experiments will unravel potential defects in peripheral auditory system in Fmr1 KO mice and provide the foundation for future in depth analyses and hypothesis-driven approaches to ameliorate sensory hypersensitivity in FXS.