Optic nerve dysfunction in a mouse model of neurofibromatosis-1 optic glioma.
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 used a genetically engineered mouse model of Nf1 optic glioma (Nf1+/-(GFAP)CKO mice). We performed multimodal functional and structural analyses both before and after the appearance of macroscopic tumors. At 6 weeks of age, before obvious glioma formation, Nf1+/-(GFAP)CKO mice had decreased visual-evoked potential amplitudes and increased optic nerve axon calibers. By 3 months of age, Nf1+/-(GFAP)CKO 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, which culminates in retinal ganglion cell death. Collectively, this study shows that Nf1+/-(GFAP)CKO mice can 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.
Hegedus
Balazs
B
Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.
Hughes
Frank W
FW
Garbow
Joel R
JR
Gianino
Scott
S
Banerjee
Debasish
D
Kim
Keunyoung
K
Ellisman
Mark H
MH
Brantley
Milam A
MA
Gutmann
David H
DH
D000367:Age Factors; D000818:Animals; D016880:Anisotropy; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods; D004195:Disease Models, Animal; D018450:Disease Progression; D004596:Electroretinography / Q000379:methods; D005074:Evoked Potentials, Visual / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism*; D009900:Optic Nerve / Q000473:pathology / Q000503:physiopathology; D020339:Optic Nerve Glioma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D010751:Phosphopyruvate Hydratase