Nogo-A inactivation improves visual plasticity and recovery after retinal injury

Author(s): Mdzomba JB (1), Jordi N (2), Rodriguez L (1), Joly S (1), Bretzner F (3), Pernet V (4)

1 CUO-Recherche, Centre de recherche du CHU de Québec and Département d'ophtalmologie, Faculté de médecine, Université Laval, Quebec, QC, Canada.
2 Department of Health Sciences and Technology, Brain Research Institute, University of Zurich, ETH Zurich, 8057, Zurich, Switzerland.
3 Centre de recherche du CHU de Québec and Département de psychiatrie et neurosciences, Faculté de médecine, Université Laval, Quebec, QC, Canada.
4 CUO-Recherche, Centre de recherche du CHU de Québec and Département d'ophtalmologie, Faculté de médecine, Université Laval, Quebec, QC, Canada. vincent.pernet.1@ulaval.ca.

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.

Cell Death Dis. 2018 Jun 27;9(7):727. doi: 10.1038/s41419-018-0780-x.

http://www.ncbi.nlm.nih.gov/pubmed/29950598

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