Abstract
Purpose :
We report further details of a mouse model for neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG) formation that exhibits developmental abnormalities of retinal electrophysiology distinguishable from OPG formation per se. Underlying mechanisms may help explain variable visual loss among children with NF1 and OPGs and lead to improved diagnosis and treatment methods.
Methods :
We refined previous analysis of relationships among visual behavior, anatomic abnormalities, and electrophysiologic activity of retinal ganglion cells (RGCs) recorded by in vitro multielectrodes in transgenic mice with neurofibromin (Nf1)-deficient glial precursors (NF1-OPG) and littermate controls. We focused on 1) early developmental abnormalities (postnatal day 11 (P11), P14, P21, and P35); and 2) retinotopic distribution of RGCs vs. their activity. We emphasized correlations among previously described patterns of RGC loss; retrobulbar hypomyelination; inter-subject and -eye differences; in vivo estimates of vision (optomotor responses, OMR) and retinal/optic nerve anatomy (optical coherence tomography, OCT); and optic nerve/chiasm histology.
Results :
Development – Prior to first eye opening, “waves” of spontaneous RGC activity are less robust in NF1-OPG mice. Retinotopic distribution – RGC density partially correlates with electrophysiologic activity, but fewer RGCs are active in NF1-OPG mice, and activity levels do not predict patterns of RGC loss. Declines in OMR-estimated visual acuity and retinal thinning on OCT correlate with RGC survival, but with moderate variability among subjects and eyes.
Conclusions :
Our findings support the existence of multiple anatomic and physiologic effects of Nf1-mutant glial precursors, several preceding OPG formation. These features may better explain vision loss in many young NF1-OPG patients that remains incompletely explained by readily observed OPG features. Future longitudinal studies may refine our understanding of the nature and relative pace of these distinct mechanisms, leading to improved identification of patients at higher risk for visual loss and to more targeted treatments.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.