Individuals with neurofibromatosis type 1 (NF1) are prone to develop optic pathway gliomas that can result in significant visual impairment. To explore the cellular basis for the reduced visual function resulting from optic glioma formation, we employed a genetically engineered mouse model of Nf1 optic glioma (Nf1+/−GFAPCKO mice). We performed multi-modal functional and structural analyses both before and after the appearance of macroscopic tumors. At 6 weeks of age, prior to obvious glioma formation, Nf1+/−GFAPCKO mice had decreased visual evoked potential amplitudes and increased optic nerve axon calibers. By 3 months of age, Nf1+/−GFAPCKO mice exhibited pronounced optic nerve axonopathy and apoptosis of neurons in the retinal ganglion cell layer. Magnetic resonance diffusion tensor imaging showed a progressive increase in radial diffusivity between 6 weeks and 6 months of age in the optic nerve proximal to the tumor indicating ongoing deterioration of axons. These data suggest that optic glioma formation results in early axonal disorganization and damage that culminates in retinal ganglion cell death. The Nf1+/−GFAPCKO mice provide a useful model for defining mechanisms of visual abnormalities in children with NF1 and lay the foundations for future interventional studies aimed at reducing visual loss.
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