Genetic Downregulation of GABAB Receptors from Oligodendrocyte Precursor Cells Protects Against Demyelination in the Mouse Spinal Cord

Abstract

GABAergic signaling and GABAB receptors play crucial roles in regulating the physiology of oligodendrocyte-lineage cells, including their proliferation, differentiation, and myelination. Therefore, they are promising targets for studying how spinal oligodendrocyte precursor cells (OPCs) respond to injuries and neurodegenerative diseases like multiple sclerosis. Taking advantage of the temporally controlled and cell-specific genetic downregulation of GABAB receptors from OPCs, our investigation addresses their specific influence on OPC behavior in the gray and white matter of the mouse spinal cord. Our results show that, while GABAB receptors do not significantly alter spinal cord myelination under physiological conditions, they distinctly regulate the OPC differentiation and Ca2+ signaling. In addition, we investigate the impact of OPC-GABAB receptors in two models of toxic demyelination, namely, the cuprizone and the lysolecithin models. The genetic downregulation of OPC-GABAB receptors protects against demyelination and oligodendrocyte loss. Additionally, we observe the enhanced resilience to cuprizone-induced pathological alterations in OPC Ca2+ signaling. Our results provide valuable insights into the potential therapeutic implications of manipulating GABAB receptors in spinal cord OPCs and deepen our understanding of the interplay between GABAergic signaling and spinal cord OPCs, providing a basis for future research.