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Genetically induced impairment of retinal ganglion cells at the axonal level is linked to extrastriate cortical plasticity

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Abstract

Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder, which leads to initially silent visual loss due to retinal ganglion cell (RGC) degeneration. We aimed to establish a link between features of retinal progressive impairment and putative cortical changes in a cohort of 15 asymptomatic patients harboring the 11778G>A mutation with preserved visual acuity and normal ocular examination. To study plasticity evoked by clinically silent degeneration of RGC we only studied mutation carriers. We phenotyped pre-clinical silent degeneration from the psychophysical, neurophysiological and structural points of view to understand whether retinal measures could be related to cortical reorganization, using pattern electrophysiology, chromatic contrast sensitivity and high-resolution optical coherence tomography to measure macular, RGC nerve fiber layer as well as inner/outer retinal layer thickness. We then performed correlation analysis of these measures with cortical thickness estimates in functionally mapped retinotopic visual cortex. We found that compensatory cortical plasticity occurring in V2/V3 is predicted by the swelling (indicating deficits of axonal transport and intracellular edema) of the macular RGC axonal layer. Increased cortical thickness (CT) in V2 and V3 was observed in peripheral regions, like visual field loss, in these mutation carriers. CT was a very discriminative measure between carriers and controls, as revealed by ROC analysis. Importantly, the substantial cortical reorganization that occurs in the carrier state can be used to provide statistical discrimination between carriers and controls to a level that is similar to measures of retinal dysfunction. We conclude that peripheral cortical compensatory plasticity in early visual areas V2/V3 may be triggered by pathology in peripheral RGC axons in combination with potential developmental changes.

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Acknowledgments

The authors thank LHON family, as well as all controls for their participation in this study. They also thank Carlos Ferreira and João Marques for helping with MRI scanning and Manuela Grazina and João Pratas for assistance in mtDNA analysis. This research was supported by Portuguese Foundation for Science and Technology Portugal [COMPETE] Strategic project Pest-C/SAU/UI3282/2011 and grants: SFRH/BD/64306/2009 (to CM), SFRH/BD/76013/2011 (to OCA); and also following grants: CENTRO-07-ST24-FEDER-00205, DoIT-Diamarker.

Conflict of interest

The authors declare that they have no conflict of interest.

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    Authors and Affiliations

    1. Visual Neuroscience Laboratory, IBILI-Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal

      Catarina Mateus, Otília C. d’Almeida, Aldina Reis & Miguel Castelo-Branco

    2. Department of Ophthalmology, Coimbra University Hospital, Coimbra, Portugal

      Aldina Reis & Eduardo Silva

    3. ICNAS, Institute for Nuclear Sciences Applied to Health, University of Coimbra, Coimbra, Portugal

      Otília C. d’Almeida & Miguel Castelo-Branco

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    1. Catarina Mateus
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    2. Otília C. d’Almeida
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    4. Eduardo Silva
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    5. Miguel Castelo-Branco
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    Correspondence to Miguel Castelo-Branco.

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    C. Mateus and O. C. d’Almeida contributed equally to this work.

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    Mateus, C., d’Almeida, O.C., Reis, A. et al. Genetically induced impairment of retinal ganglion cells at the axonal level is linked to extrastriate cortical plasticity. Brain Struct Funct 221, 1767–1780 (2016). https://doi.org/10.1007/s00429-015-1002-2

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