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

Abstract

Neurofibromin gene (<i>NF1</i>) 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, <i>Nf1</i> 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 <i>Nf1</i> gene inactivation in adult oligodendrocytes (Plp-<i>Nf1</i>^fl/+ mice) results in a motor coordination deficit. Magnetic resonance imaging in awake mice showed that fractional anisotropy is reduced in Plp-<i>Nf1</i>^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.