ALBERT

Description: Publication date: Available online 12 September 2013 Source: Cell Reports Author(s): Debra A. Mayes , Tilat A. Rizvi , Haley Titus-Mitchell , Rachel Oberst , Georgianne M. Ciraolo , Charles V. Vorhees , Andrew P. Robinson , Stephen D. Miller , Jose A. Cancelas , Anat O. Stemmer-Rachamimov , Nancy Ratner Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1–NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients. Graphical abstract Teaser In this study, Ratner and colleagues show that altering intracellular signaling in oligodendrocytes affects brain astrocytes and blood vessels that together make up the blood-brain barrier. Increasing oligodendrocyte Ras-GTP, mimicking neurofibromatosis type 1 and Costello syndrome, disrupted astrocyte and endothelial cell tight junctions and gap junctions and caused a leaky blood-brain barrier. Exposure to a nitric oxide synthase inhibitor or an antioxidant reversed cellular phenotypes and behavioral hyperactivity. Thus, oligodendrocytes contribute to brain homeostasis, and antioxidant therapy may be beneficial when homeostasis is disrupted.