Brain-wide structural and functional disruption in mice with oligodendrocyte-specific Nf1 deletion is rescued by inhibition of nitric oxide synthase.

Neurofibromin gene (NF1) mutation causes neurofibromatosis type 1 (NF1), a disorder in which brain white matter deficits identified by neuroimaging are common, yet of unknown cellular etiology. In mice, Nf1 loss in adult oligodendrocytes causes myelin decompaction and increases oligodendrocyte nitric oxide (NO) levels. Nitric oxide synthase (NOS) inhibitors rescue this pathology. Whether oligodendrocyte pathology is sufficient to affect brain-wide structure and account for NF1 imaging findings is unknown. Here we show that Nf1 gene inactivation in adult oligodendrocytes (Plp-Nf1 fl/+ mice) results in a motor coordination deficit. Magnetic resonance imaging in awake mice showed that fractional anisotropy is reduced in Plp-Nf1 fl/+ corpus callosum and that interhemispheric functional connectivity in the motor cortex is also reduced, consistent with disrupted myelin integrity. Furthermore, NOS-specific inhibition rescued both measures. These results suggest that oligodendrocyte defects account for aspects of brain dysfunction in NF1 that can be identified by neuroimaging and ameliorated by NOS inhibition.