Oral 1821-3 - Ras Signaling and No in Oligodendrocytes Modulate Permeability of the Blood–Brain Barrier

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Background: Ras is a small G-protein switch, activated when GTP-bound; in the GTP-bound state Ras signals to downstream effector proteins. GTPase inactivating proteins (GAPs) including neurofibromain (Nf1) accelerate hydrolysis of Ras-GTP to inactive Ras-GDP. We showed that activation of Ras or loss of Nf1 in brain oligodendrocytes correlates with myelin decompaction, down-regulation of claudins, and down-regulation and mis-localization of connexins (Mayes et al., Cell Reports, 2013). Non-cell autonomous defects in perivascular astrocytes and blood–brain barrier (BBB) are also observed. The blood–brain barrier becomes leaky, implicating a soluble mediator. NO and nitric oxide synthases (NOS1-3) are up-regulated in mutant white matter. Treating mice with the NOS inhibitor L-NAME or the antioxidant NAC corrected cellular phenotypes. Consistent with recent data implicating white matter changes in learning, CNP-HRasG12V mice displayed locomotor hyperactivity which could be rescued by antioxidant treatment.

Results: Using flow cytometry to define reactive species in cells in sorted brain non-neuronal cells we have now identified alterations in reactive species (NO, SO and/or peroxynitrites) in oligodendrocyte precursors, oligodendrocytes, astrocytes, pericytes and endothelial cells when Ras-GTP is elevated in oligodendrocytes. We also found that many changes are absent in Nf1+/− mice, when cells in the brain in addition to oligodendrocytes are hemizygous for Nf1 loss. Mating mice in which oligodendrocyte only have activated Ras with Nf1+/− mice confirmed that effects on reactive species are mediated by hemizygosity in Nf1+/− astrocytes, pericytes and/or endothelial cells. FACs analysis showed that NO is significantly diminished in oligodendrocytes in these mutants, and shuttled to surrounding cells of the vasculature.

Conclusion: We conclude that signaling between oligodendrocytes and cells of white matter blood vessels contributes to homeostasis of the blood–brain barrier.

NR is supported by the NIH, the DOD Program in Neurofibromatosis and the Children's Tumor Foundation.



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