Visual Sensorial Impairments in Neurodevelopmental Disorders: Evidence for a Retinal Phenotype in Fragile X Syndrome

Abstract

Visual sensory impairments are common in Mental Deficiency (MD) and Autism Spectrum Disorder (ASD). These defects are linked to cerebral dysfunction in the visual cortical area characterized by the deregulation of axon growth/guidance and dendrite spine immaturity of neurons. However, visual perception had not been addressed, although the retina is part of the central nervous system with a common embryonic origin. Therefore, we investigated retinal perception, the first event of vision, in a murine model of MD with autistic features. We document that retinal function is altered in Fmr1 KO mice, a model of human Fragile X Syndrome. Indeed, In Fmr1 KO mice had a lower retinal function characterized by a decreased photoreceptors neuron response, due to a 40% decrease in Rhodopsin content and to Rod Outer Segment destabilization. In addition, we observed an alteration of the visual signal transmission between photoreceptors and the inner retina which could be attributed to deregulations of pre- and post- synaptic proteins resulting in retinal neurons synaptic destabilization and to retinal neurons immaturity. Thus, for the first time, we demonstrated that retinal perception is altered in a murine model of MD with autistic features and that there are strong similarities between cerebral and retinal cellular and molecular defects. Our results suggest that both visual perception and integration must be taken into account in assessing visual sensory impairments in MD and ASD.

Fragile X Mental Retardation Protein expression in the retina is regulated by light

“…It would probably help us understand some distinguished behaviors that Fragile X Syndrome individuals present that may be caused by vision rather than cognition-related problems. It should also reinforce the hypothesis (Rossignol et al, 2014) that the overall “sensorial hypersensitivity” phenotype of Fragile X Syndrome is not only due to the well-known cerebral defects, but also to sensorial perception defects through the peripheral sensorial tissue.…”

“…Such plasticity events have been described in the retina as well, and could account for modifications in retinal ganglion cell rectification currents (Jones et al, 2012). One recent paper has shown that FMRP is expressed in the retina and that its absence correlates with increases in the electroretinogram b-wave, which mostly reflects ON-bipolar cell depolarization to light (Rossignol et al, 2014). FMRP thus appears to influence retinal physiology.…”

“…We used rabbit anti-FMRP polyclonal antibody (ab17722, Abcam, validated in the Fmr1 knockout mouse by Rossignol et al, 2014), 2F5 mouse anti-FMRP monoclonal antibody (a kind gift from Dr. Kimberly Huber, validated in the Fmr1 knockout mouse by Gabel et al, 2004), and rabbit phospho-FMRP polyclonal antibody (p1125-499, Phosphosolutions). Phospho-FMRP (or pFMRP) antibody was validated by Western blot and immunohistochemistry in wildtype and Fmr1 knockout mice (Supplementary material, Figures 1S and 2S).…”

Retinal alterations in a pre-clinical model of an autism spectrum disorder

“…5 and 6) and since the sensitivity (k) and slope (n) of the a-wave intensity-response relation are unchanged in the VPA model. Such a decrease in the maximal amplitude with no concomitant change in the sensitivity or gain of the ERG a-wave was also described in the Fmr1 −/− mouse, an animal model with ASD-like behaviors that lacks the FMRP protein, among other retinal alterations [43,44], and points to the possibility that the phototransduction machinery within photoreceptors may be changed in the VPA model. Furthermore, since (i) the a-wave is contributed to by both rods and cones [30,34], (ii) rods contribute more to the ERG at low light levels, whereas cones contribute more at higher light levels [30,34], and (iii) our results show a larger effect at high light intensities, it is likely that cones are more affected than rods in VPA-exposed animals.…”

Transcriptome Analyses of lncRNAs in A2E-Stressed Retinal Epithelial Cells Unveil Advanced Links between Metabolic Impairments Related to Oxidative Stress and Retinitis Pigmentosa

“…Thus, the over-expression of PINK1-AS could represent an oxidative stress induced signal reflecting the apoptotic status of treated RPE cells. In the meantime, the down-expression of both FMR1-IT1 and VIM-AS1, related to synaptogenesis, intracellular trafficking and cellular stability [104,105], could be seen as a final attempt of RPE cells to boost the production and sorting of vital proteins towards the most essential cellular districts. Additionally, nine miRNAs interacting with several down-regulated lncRNAs resulted involved in lysine degradation pathway.…”