Abstract
Myelin-associated proteins such as Nogo-A are major inhibitors of neuronal plasticity that contribute to permanent neurological impairments in the injured CNS. In the present study, we investigated the influence of Nogo-A on visual recovery after retinal injuries in mice. Different doses of N-methyl-d-aspartate (NMDA) were injected in the vitreous of the left eye to induce retinal neuron death. The visual function was monitored using the optokinetic response (OKR) as a behavior test, and electroretinogram (ERG) and local field potential (LFP) recordings allowed to assess changes in retinal and cortical neuron activity, respectively. Longitudinal OKR follow-ups revealed reversible visual deficits after injection of NMDA ≤ 1 nmole in the left eye and concomitant functional improvement in the contralateral visual pathway of the right eye that was let intact. Irreversible OKR loss observed with NMDA ≥ 2 nmol was correlated with massive retinal cell death and important ERG response decline. Strikingly, the OKR mediated by injured and intact eye stimulation was markedly improved in Nogo-A KO mice compared with WT animals, suggesting that the inactivation of Nogo-A promotes visual recovery and plasticity. Moreover, OKR improvement was associated with shorter latency of the N2 wave of Nogo-A KO LFPs relative to WT animals. Strikingly, intravitreal injection of anti-Nogo-A antibody (11C7) in the injured eye exerted positive effects on cortical LFPs. This study presents the intrinsic ability of the visual system to recover from NMDA-induced retinal injury and its limitations. Nogo-A neutralization may promote visual recovery in retinal diseases such as glaucoma.
Highlights
Retinal degeneration resulting from stroke, diabetic retinopathy, or glaucoma causes irreversible vision loss by inducing neuronal cell death
The optokinetic response (OKR) of adult WT mice was assessed after intravitreal injections of variable concentrations of NMDA into the left eye
The spatial frequency threshold assessed after NMDA delivery allowed to distinguish three patterns of functional changes: (1) at 0.02–0.1 nmol NMDA—weak visual response reduction and quick and complete recovery; (2) at 0.2–1 nmol NMDA—transient visual response abolition followed by delayed recovery; and (3) at 2–10 nmol NMDA—permanent visual response abolition (Fig. 1c)
Summary
Retinal degeneration resulting from stroke, diabetic retinopathy, or glaucoma causes irreversible vision loss by inducing neuronal cell death. Retinal disease models showed that the extent of visual deficits does not always correlate with the level of retinal cell death[1,2]. Functional impairments in surviving neurons may account to a large extent for visual deficits after retinal injury. The fact that retinal neurons have a very weak ability to regenerate after injury is likely to participate in the vision deterioration caused by ocular diseases[3,4,5]. Molecular mechanisms restricting visual neuron plasticity have been described in the injured retina.
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