Peripheral Neuron Excitability is Mediated by Schwann cells in Fabry disease

Abstract

Fabry disease (FD) is a genetic lysosomal storage disease in which patients experience life-long and debilitating neuropathic pain. Patients with FD are typically diagnosed with painful peripheral neuropathy, and peripheral nerves from patients with FD exhibit morphological abnormalities in multiple cell types, including Schwann cells. In other painful disease models, evidence suggests that dysfunctional Schwann cells may influence neuronal function by releasing algogenic soluble mediators. It is unclear whether dorsal root ganglia (DRG) neurons from FD exhibit functional changes in neuronal excitability, and if altered Schwann cell signaling influences these functional changes. To address this, we cultured both DRG neurons and Schwann cells from a genetic rat model of FD. Using in-vitro calcium imaging, we determined that a greater percentage of DRG neurons from FD rats responded to an acute exposure of a depolarizing stimuli; high extracellular KCl. Furthermore, our preliminary data suggests DRG neurons from FD rats exhibit increased excitability via whole-cell patch clamp electrophysiology. Next, we determined if FD Schwann cells contribute to this enhanced neuronal excitability. We first confirmed that FD rats exhibit Schwann cell pathology using electron microscopy, similar to findings observed in FD patient tissue samples. Subsequent calcium imaging analysis revealed that when exposed to soluble mediators derived from FD Schwann cells, wildtype DRG neuron responses to high extracellular KCl were enhanced. In conclusion, these data suggest that DRG neurons from FD rats are hyperexcitable and that the Schwann cell secretome may drive this change in excitability. Analysis of the Schwann cell secretome could lead to novel targets for the alleviation of ongoing pain in FD, and further our understanding of the role of Schwann cells in chronic pain. Grant support from R37-NS108278-03 F31-NS122380-01.