Abstract
Purpose :
N-Methyl-D-Aspartate receptor (NMDAR) over-activation mediates retinal dysfunction in major diseases such as diabetic retinopathy. We have previously observed that blocking Nogo-A, a potent myelin-associated inhibitor, reduced the deleterious effects of retinal ischemia on the neuronal survival and function of juvenile mice. The contribution of Nogo-A to development of visual deficits is not clear in adult animals. Therefore, the aim of the current study was to investigate the role of Nogo-A in NMDA excitotoxicity-induced visual impairments in the adult mouse.
Methods :
0.5-40 nmol of NMDA was administered by intravitreal injection to produce different levels of retinal injury. Nogo-A’s function was blocked by using either knock-out (KO) mice or by intravitreally injecting a function-blocking antibody (11C7) two days after NMDA injection. Visual function was followed using the optokinetic reflex (OKR) and electroretinogram (ERG) recordings. Cortical activity was monitored through local field potential (LFP) recording in the visual cortex. Immunofluorescence on retinal flat-mounts was used for cell survival analysis.
Results :
OKR and immunofluorescence assessments showed that injection of low concentrations (~0.5 nmol) of NMDA produced damage limited to the ganglion cell layer (GCL), consisting of a drop of ~20 % in visual acuity and a ~30-% ganglion cell (GC) loss. Higher concentrations of NMDA resulted in damage generalized to the whole retina: GC loss reached ~80%, visual acuity dropped by ~80% and ERG b-wave amplitudes decreased by half. Strikingly, we observed a better functional recovery in Nogo-A KO mice after excitotoxic injury induced with 0.5 nmol of NMDA. Similar improvements were obtained after intravitreal injection of 11C7. The latency of LFP was reduced in KO and in 11C7-treated mice when compared to control WT and control IgG-treated mice, suggesting enhanced visual cortex function after Nogo-A inactivation. However, 11C7 did not significantly influence RGC survival and the ERG response.
Conclusions :
Our data suggest that Nogo-A is implicated in the emergence of visual deficits after retinal injury. Antibody-based neutralization of Nogo-A may stimulate visual recovery in retinal diseases involving excitotoxic cell death such as diabetic retinopathy.
This is a 2020 ARVO Annual Meeting abstract.