Gobbo Davide, Rieder Phillip, Fang Li-Pao, Buttigieg Emeline, Schablowski Moritz, Damo Elisa, Bosche Nathalie, Dallorto Eleonora, May Pascal, Bai Xianshu, Kirchhoff Frank, Scheller Anja
Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, 66421 Homburg, Germany.
Institut des Neurosciences de la Timone (INT), Aix-Marseille Université, CNRS UMR7289, 13005 Marseille, France.
Cells. 2024 Dec 5;13(23):2014. doi: 10.3390/cells13232014.
GABAergic signaling and GABA 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 GABA 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 GABA receptors do not significantly alter spinal cord myelination under physiological conditions, they distinctly regulate the OPC differentiation and Ca signaling. In addition, we investigate the impact of OPC-GABA receptors in two models of toxic demyelination, namely, the cuprizone and the lysolecithin models. The genetic downregulation of OPC-GABA receptors protects against demyelination and oligodendrocyte loss. Additionally, we observe the enhanced resilience to cuprizone-induced pathological alterations in OPC Ca signaling. Our results provide valuable insights into the potential therapeutic implications of manipulating GABA 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.
γ-氨基丁酸（GABA）能信号传导和GABA受体在调节少突胶质细胞系细胞的生理过程中发挥着关键作用，包括其增殖、分化和髓鞘形成。因此，它们是研究脊髓少突胶质前体细胞（OPC）如何应对损伤和诸如多发性硬化症等神经退行性疾病的有前景的靶点。利用对OPC中GABA受体进行时间控制和细胞特异性基因下调的方法，我们的研究探讨了它们对小鼠脊髓灰质和白质中OPC行为的特定影响。我们的结果表明，虽然GABA受体在生理条件下不会显著改变脊髓髓鞘形成，但它们能明显调节OPC分化和钙信号传导。此外，我们在两种毒性脱髓鞘模型，即铜螯合剂和溶血卵磷脂模型中研究了OPC-GABA受体的影响。OPC-GABA受体的基因下调可防止脱髓鞘和少突胶质细胞丢失。此外，我们观察到OPC钙信号传导对铜螯合剂诱导的病理改变的恢复力增强。我们的结果为操纵脊髓OPC中的GABA受体的潜在治疗意义提供了有价值的见解，并加深了我们对GABA能信号传导与脊髓OPC之间相互作用的理解，为未来的研究提供了基础。
