ROLE OF NEURITIN 1 IN RESPONSE TO OPTIC NERVE CRUSH

Purpose: Glaucoma is a progressive optic neuropathy characterized by axonal injury, retinal ganglion cell (RGC) loss, and visual field defects. Neuritin1 (Nrn1) is an extracellular, GPI-linked protein, which can be secreted as a soluble form. It stimulates axonal plasticity, dendritic arborization, and synapse maturation in the CNS. The purpose of this study was to evaluate the expression of Nrn1 in an in vivo optic nerve crush (ONC) mouse model that mimics features of glaucoma axonopathy. Methods: Unilateral ONC was performed on 8-10-week-old BALB/cJ eyes using the Nickell's technique. Retinas (N=8/group) and ONs (N=6/group) were harvested at six different time points (0, 3, 7, 14, 21, and 28 days post crush) (dpc). Real time PCR and immunohistochemistry (IHC) was performed to spatially and temporally evaluate Nrn1 expression in the retina and ON. Results: After ONC, Nrnl gene expression in the retina significantly decreased by 7 dpc compared to control eyes, with slight recovery by 14 dpc and then a significant reduction by 21 dpc (p<0.05, fold change of 1.5). In contrast, we observed basal expression until 21 dpc in the ON, with a significant increase at 28 dpc (p<0.05, fold change of 1.5). Biphasic expression patterns were observed in both retina and ON IHC sections. Conclusions: Axonopathy and degeneration of neurons and axonopathy are classical hallmarks of glaucoma neuropathy and also occur in other neurodegenerative diseases such as Parkinson and Alzheimer's. Nrn1, a vital player in neuronal plasticity, exhibited a biphasic expression pattern after ONC suggesting that modifications in regenerative ability of neurons lead to RGC and ON axonal injury. Future studies will determine whether Nrn1 gene therapy can prevent the loss of neurons by reviving regeneration after optic nerve axonopathy.