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Objective RGC loss is reported in many optic neuropathies, such as glaucoma, ischemia, et al.Since RGCs transmit the information processed by the retina to higher visual centers, loss of RGCs inevitably leads to impairment of visual functions.BDNF is one of the most potent and most frequently used neurotrophic factors, widely applied in both protection and rescue of RGCs.Adeno-associated virus (AAV) is by far most suitable viral vector for gene therapy because of sustained expression and safety.In this study, we asked whether AAV mediated BDNF expression is possible to rescue RGCs after acutely elevated intraocular pressure, furthermore, supplement the gene therapy with BDNF protein to compensate the slow onset of AAV mediated expression? If BDNF did rescue RGCs, then what is the mechanism? Methods Rat model was established with acute elevation of intraocular pressure, followed by intravitreal injection of BDNF-expressing AAV vectors and/or BDNF protein.Rescue effect of RGCs and visual function was evaluated by quantification of surviving RGCs, visual evoked potential recording and visual behavior test based on two-alternative swimming task.Results Retinal ganglion ceils (RGCs) underwent a continuous loss up to nine weeks after the intraocular pressure was elevated to 135 mmHg for 45 min.We constructed an AAV vector to express BDNF to rescue RGCs.AAV mediated BDNF expression significantly rescued RGCs and visual functions.Supplementing BDNF protein to compensate the slow onset of exogenous gene expression achieved a much greater rescue effect.But administering BDNF without gene therapy, RGCs still underwent a significant reduction at the end of 9th week.We further demonstrated that BDNF rescued RGCs through activating TrkB receptors through autocrine and paracrine mechanisms to improve axon transport.Significant improvements in visual function were apparent in increased amplitude and decreased latency of P1 component of visual evoked potential.And in behavioral tests, visual acuity and contrast sensitivity were significantly increased in the group of combined therapy and sustained for 30 weeks without causing any apparent discomfort.Conclusion Expression BDNF using an AAV vector can significantly rescue RGCs and visual functions, and supplementing BDNF protein with gene therapy achieved an astonishing effect in number of RGCs and visual functions rescued.BDNF act via TrkB receptors through autocrine and paracrine to improve axon transport to achieve the rescue.