The Effect of Functional Electrical Stimulation on Oligodendrocyte Biology after Spinal Cord Injury
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In the developing and adult central nervous system (CNS), oligodendrocyte (OL) biology is controlled intrinsically by transcription and epigenetic factors, and extrinsically by neural activity and signaling molecules. Neural activity regulates OL development through the release of neurotransmitters and soluble molecules such as glutamate, ATP, and LIF. The epigenome controls gene expression through DNA methylation and post-transcriptional repression by microRNAs (miRs). These signaling pathways are dysregulated following CNS injury or disease, making them potential targets for therapeutic intervention. However, the effect of patterned neural activity on OL development and epigenetic mechanisms after spinal cord injury (SCI) is not fully understood. We found that the application of functional electrical stimulation (FES) after a complete mid-thoracic SCI in adult rats enhances proliferation of oligodendrocyte progenitor cells (OPCs) in the lumbar spinal cord in a frequency-dependent manner. Our data show that SCI alters miR expression caudal to the lesion level, and that FES treatment delays the injury-induced repression of OL-specific miR-338 and miR-23a. Furthermore, FES promotes the upregulation of miR-19b and DNA methyltransferases 1 and 3b, which are associated with neurogenesis and oligodendrogenis in the CNS. Taken together, these results suggest that neural activity regulates OL development in the injured spinal cord by modulating epigenetic mechanisms.