Background & Aims
Fragile X syndrome (FXS) is the leading known genetic cause of intellectual disability and autism. Some of the most prevalent symptoms of FXS is hypersensitivity to sensory stimuli and self-injurious behaviors, indicative of abnormal pain perception (1). These deficits have thus far been largely attributed to sensory processing deficits in brain circuits (1,2). Yet, despite two decades of intensive studies, mechanisms of pain perception deficits in FXS remain poorly understood. Activity of peripheral sensory neurons in dorsal root ganglia (DRG) has long been implicated in pain perception. It is modulated by satellite glial cells (SGCs), which completely envelop each sensory neuron soma to provide bi-directional communication and feed-back control of neuronal activity (3-5). Dysregulation of SCG-neuron communication is known to contribute to many pain syndromes (6-8). Yet, whether SGCs contribute to sensory and pain deficits in FXS remains poorly understood.
Methods
Fmr1 KO and WT control mice on FVB background were obtained from The Jackson Laboratory. Whole-cell patch-clamp recordings were performed using a Multiclamp 700B amplifier from short-term cultures visually identified with differential interference contrast optics. Recordings were conducted at near-physiological temperature (33–34?°C), and made from DRG neurons both with and without SGCs. The DRG neurons associated with at least 1 glial cell were counted as neuron with SGCs. In these conditions, the majority of cells analyzed are small/medium diameter IB4-positive nociceptors (10). Data are means ± SEM. Student’s t test or KS test were used for statistical analysis as appropriate. We thank Dr. Oshri Avraham for providing cell cultures for these experiments.
Results
We have recently found that cultured peripheral sensory neurons exhibit pronounced hyperexcitability in FXS mice and that association between SGCs and sensory neurons is disrupted in FXS mouse model at the ultrastructural level (9,10). Moreover, both sensory neurons and glia show marked transcriptional changes, including altered calcium signaling and secretion pathways in both cell types. Therefore, we asked whether SGCs play a role in the altered excitability of sensory neurons in the absence of FMRP and may thus contribute to the abnormal pain perception in this disorder.
To address this question, we utilized an adult sensory neuron-SGC co-culture model system and examined excitability of sensory neurons that were associated with SCGs versus the neurons that were not associated with SGCs. We verified with the specific SGC marker, FABP7, that when a neuron was associated with other cells, these cells were SGCs in vast majority of the cases. We found that the alterations in sensory neuron excitability, including the reduction of the rheobase in FXS neurons was partially yet significantly compensated in the presence of SGCs, suggesting that SGCs play a protective role in maintaining sensory neuron excitability in FXS mice.
Conclusions
These studies suggest that SGCs play a critical protective role in maintaining excitability of sensory FXS neurons. Our findings open new directions to ameliorate sensory and pain deficits in FXS by improving the SGC-sensory neuron communication.
References
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