Neurotrophic factors impart functional protection to the retina against ocular hypertension

Purpose: TrkB signalling plays a critical role in the maintenance of retinal integrity. TrkB dimerization and autophosphorylation lead to activation of pro-survival cell signalling pathways that can afford neuroprotection to retinal ganglion cells (RGCs). We investigated functional changes in the retinas of mice with impaired TrkB downstream signalling in response to exposure to increased intraocular pressure, and determined whether augmenting the TrkB signalling using a specific agonist 7,8-dihydroxyflavone (7,8-DHF), can prevent this functional loss in experimental glaucoma. Methods: A unilateral chronic ocular hypertensive model was established by weekly microbead injections into the anterior chamber of adult B6.129S4-Bdnftm1Jae/J heterozygous mice with wildtype as control. 7,8-DHF was administered weekly to another set of mice with unilaterally increased IOP for 8 weeks. Electroretinogram (ERG) and scotopic threshold response (STR) measurements were performed to assess retinal function. Results: Exposure to increased intraocular pressure leads to a decline in the inner retinal function (STR amplitudes) in both wildtype (p < 0.04) and heterozygous (p < 0.004) mice. Heterozygous mice were however more susceptible to the decline in the inner retinal function compared to their wildtype counterparts (p < 0.04). Administration of 7,8-DHF prevented the loss of STR amplitudes to a greater extent in heterozygous mice (p < 0.001). Scotopic ERG recordings were not significantly altered in any of the cases. Conclusion: This study demonstrates that the TrkB signalling plays an important role in protecting retinal ganglion cell function in glaucoma and that the detrimental effects of TrkB downstream deficiency can be compensated by exogenous administration of 7,8-DHF – a TrkB agonist.