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

Pediatric low-grade glioma (pLGG) is the most common brain tumor in children, and 14% of pLGG tumors arise from individuals with neurofibromatosis type 1 (NF1), which frequently develops along the optic nerve, optic chiasm, and optic tract. These familial pLGGs are collectively referred to as NF1-associated optic pathway gliomas (NF1-OPGs), occurring in nearly 20% of NF1 patients; 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. Radiation therapy on NF1 patients carries the risk of mortality due to secondary malignant neoplasms or vascular injury. The current standard-of-care treatment for NF1-OPG is chemotherapy using non-alkylating agents, 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. The novel research and therapeutic strategies are urgently needed. Although vision loss is the most severe symptom in NF1-OPG patients, the retinal pathophysiology behind this loss has not been well characterized. We studied a well-established NF1-OPG model (Nf1-hGFAP-CKO) and found that, similar to NF1 patients, this NF1-OPG model exhibited tumor-associated loss of RGCs. We quantified the RGC loss at different ages and performed MEA recordings on retinas from mutant mice to characterize their physiological abnormalities. We discovered several patterns of RGC lost, including segmental lost, diffuse lost, and parapapillary lost. We also observed abnormal microglia/macrophage infiltration as early as P15 at the area of tumor formation near the optic chiasm and microglia activation in the retina at later time points. In addition, we assessed the visual/behavioral and anatomical abnormalities of NF1-OPG mice using the optomotor response (OMR) and OCT assay respectively, further confirming the functional consequence of RGC defects in NF1-OPG mice. These results provide a foundation for further investigation of the mechanisms of NF1-OPG induced vision defects and potential new therapeutic targets.