Early Retinal Defects in Fmr1−/y Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype?

Abstract

Fragile X Syndrome (FXS) is caused by a deficiency in Fragile X Mental Retardation Protein (FMRP) leading to global sensorial abnormalities, among which visual defects represent a critical part. These visual defects are associated with cerebral neuron immaturity especially in the primary visual cortex. However, we recently demonstrated that retinas of adult Fmr1−/y mice, the FXS murine model, present molecular, cellular and functional alterations. However, no data are currently available on the evolution pattern of such defects. As retinal stimulation through Eye Opening (EO) is a crucial signal for the cerebral visual system maturation, we questioned the precocity of molecular and functional retinal phenotype. To answer this question, we studied the retinal molecular phenotype of Fmr1−/y mice before EO until adult age and the consequences of the retinal loss of Fmrp on retinal function in young and adult mice. We showed that retinal molecular defects are present before EO and remain stable at adult age, leading to electrophysiological impairments without any underlying structural changes. We underlined that loss of Fmrp leads to a wide range of defects in the retina, settled even before EO. Our work demonstrates a critical role of the sensorial dysfunction in the Fmr1−/y mice overall phenotype, and provides evidence that altered peripheral perception is a component of the sensory processing defect in FXS conditions.

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

“…Importantly, these animals present significant alterations in the full-field scotopic ERG, suggesting photoreceptor dysfunctions, with cones probably more affected than rods. These functional alterations are accompanied by compensatory mechanisms in the post-receptoral circuitry, which are consistent with the structural changes that we report in this model and in the literature dealing with other ASD models [43,44]. It remains to be shown how these animals respond to different stimulation protocols, such as the photopic and pattern ERGs, which test cone-driven pathways and the inner retina, respectively [62,63].…”

“…These results indicate that adaptive changes are probably taking place in both synaptic layers of the retina in order to adjust the gain of these synapses and to compensate for the smaller photoreceptor input. Comparatively similar compensatory mechanisms in the signal transmission from the outer to the inner retina were also described in the ERGs of the Fmr1 −/− mouse [43,44] and were shown to have very early onset in development [44]. Our ERG results are therefore consistent with the work of others and also with the altered expression of synaptic proteins in the outer and inner retina of VPA mice that we report here.…”

“…Therefore, FMRP expression changes might lead to alterations in physiological responses of retinal neurons. In fact, Fmr1 −/− animals present functional changes in both outer and inner retinal anatomy and function [43,44]. Accordingly, our results show that not only does the retina of the VPA-exposed mice express less FMRP than control mice, but it also displays morphological and physiological features similar to the Fmr1 −/− model.…”

“…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.…”

Cellular localization of the FMRP in rat retina

“…This protein has been proved to be ubiquitously produced in mammalian tissues with high levels in the brain [40] and localized predominantly in cytosolic light and heavy membranes. Furthermore, the retina is part of the central nervous system with a common embryonic origin, the mechanisms in the signal transmission from outer to inner retina were described in the ERGs of the Fmr1 −/− mouse [23,41], and were shown to have very early onset in development [41].…”