Functional and anatomical characterizations of retinal ganglion cell degeneration in a murine model of Neurofibromatosis type 1

National Eye Institute

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Abstract

Patients with neurofibromatosis type 1 (NF1) often develops glioma along the optic nerve, optic chiasm, and optic tract, referred to as NF1-associated optic pathway gliomas (NF1-OPGs). They are the most common tumor type in the central nervous system (CNS) associated with NF1. Due to the location and extensive involvement of OPG along the optic pathway, surgery would cause vision loss and rarely is a therapeutic option. The current standard-of-care treatment for NF1-OPG is chemotherapy, which can control tumor growth, but visual outcomes are variable. Thus, the standard oncology approaches for NF1-OPG are not sufficient to improve visual impairment the major morbidity associated with this tumor type. Although vision loss is the most severe symptom in NF1-OPG patients, the retinal pathophysiology behind this loss has not been well characterized. We have imported a well-established NF1-OPG model (Nf1hGFAPCKO) from our collaborator (Dr. Yuan Zhu, Childrens National). Our preliminary results suggest that, similar to NF1 patients, this NF1-OPG model exhibited tumor-associated loss of RGCs with visual/behavioral and anatomical abnormalities, detected by the optomotor response (OMR) and OCT assay, respectively. We quantified the RGC loss at different ages and observed significant RGC loss at P30. By P120, some only have 20% RGC left. We performed MEA recordings on retinas from mutant mice and characterize their physiological abnormalities. Intriguingly, we observed a sectorial RGC degeneration pattern, similar to that of glaucoma patients. More importantly, we observed abnormal microglia/macrophage infiltration as early as P15 at the area of tumor formation near the optic chiasm; we also observed microglia activation in the retina at later time points. Based on these data, we hypothesize that NF1-OPG induces microglia/macrophage activation and leads to a pathology similar to other forms of optic neuropathies, such as optic nerve injury and glaucoma. We will further investigate the mechanism of tumor-induced inflammatory microglial responses which leads to RGC degeneration in NF1-OPG.