Abstract
Purpose :
The transmembrane protein Nogo-A is a potent inhibitor of neuronal plasticity and repair. After CNS injury, Nogo-A prevents the cytoskeleton rearrangements required for functional rewiring of neuronal circuits. Its neutralization can support axonal regeneration and neuronal recovery. The goal of this study was to investigate the role of Nogo-A in the visual impairments induced by N-Methyl-D-Aspartate-induced (NMDA) excitotoxicity in the adult mouse. Excitotoxic damage is thought to be a major pathological mechanism causing retinal dysfunction in ocular diseases. In addition, we evaluated Nogo-A expression changes in diabetic human retinae.
Methods :
Different levels of retinal injury were induced by intravitreal injection of 0.5-40 nmol of NMDA. Nogo-A’s function was blocked by using either knock-out (KO) mice or by intravitreally injecting a highly specific monoclonal function-blocking antibody (11C7) two days after NMDA injection. Visual function was followed using the optokinetic response (OKR) and by electroretinogram (ERG) recordings. Visual cortex activity was monitored through local field potential (LFP) recording. Immunofluorescence on retinal flat-mounts and on retinal sections was used to observe neuronal survival and Nogo-A expression changes.
Results :
Intravitreal administration of 0.5nmol of NMDA produced damage limited to the ganglion cell layer (GCL), consisting of a drop of ~20 % in OKR spatial sensitivity and a ~30-% reduction in the number of ganglion cells (GC). 5nmols of NMDA produced extended destruction in the inner retina, as shown by the loss of ~80% of GC, the decrease of OKR spatial sensitivity by ~80%, and the decrease of the ERG b-wave amplitude by ~50%. Nogo-A KO mice and animals intravitreally injected with 11C7 showed a marked OKR spatial sensitivity improvement after NMDA-induced injury. In the same experimental groups, reduced LFP latency suggested enhanced visual cortex activation in response to eye stimulation with light flashes. However, 11C7 did not significantly influence GC survival. In human diabetic eyes, Nogo-A was overexpressed, suggesting its possible contribution to visual deterioration in ocular diseases affecting GC.
Conclusions :
Our data suggest that Nogo-A is implicated in the development of permanent visual deficits caused by retinal injury. Intravitreal administration of Nogo-A-neutralizing antibodies may promote visual recovery in retinal diseases such as diabetic retinopathy.
This is a 2021 ARVO Annual Meeting abstract.