Maria‐Paz Villegas‐Pérez

To investigate the short- and long-term effects of axotomy on the survival of central nervous system (CNS) neurons in adult rats, retinal ganglion cells (RGCs) were labelled retrogradely with the persistent marker diI and their axons interrupted in the optic nerve (ON) by intracranial crush 8 or 10 mm from the eye or intraorbital cut 0.5 or 3 mm from the eye. Labelled RGCs were counted in flat-mounted retinas at intervals from 2 weeks to 20 months after axotomy. Two major patterns of RGC loss were observed: (1) an initial abrupt loss that was confined to the first 2 weeks after injury and was more severe when the ON was cut close to the eye; (2) a slower, persistent decline in RGC densities with one-half survival times that ranged from approximately 1 month after intraorbital ON cut to 6 months after intracranial ON crush. A small population of RGCs (approximately 5%) survived for as long as 20 months after intraorbital axotomy. The initial loss of axotomized RGCs presumably results from time-limited perturbations related to the position of the ON injury. A persistent lack of terminal connectivity between RGCs and their targets in the brain may contribute to the subsequent, more protracted RGC loss, but the differences between intraorbital cut and intracranial crush suggest that additional mechanisms are involved. It is unclear whether the various injury-related processes set in motion in both the ON and the retina exert random effects on all RGCs or act preferentially on subpopulations of these neurons.

Inherited photoreceptor degeneration in humans constitutes a major cause of irreversible blindness in the world. They comprise various diseases, but retinitis pigmentosa is the most frequently observed. Retinitis pigmentosa is commonly limited to the eye, where there is progressive photoreceptor degeneration, rods and secondarily cones. The mechanisms of cone and rod degeneration continue to be investigated, since most of the mutations causing retinitis pigmentosa affect rods and thus, the secondary death of cones is an intriguing question but, ultimately, the cause of blindness. Understanding the mechanisms of rod and cone degeneration could help us to develop therapies to stop or, at least, slow down the degeneration process. Secondary cone degeneration has been attributed to the trophic dependence between rods and cones, but microglial cell activation could also have a role. In this review, based on previous work carried out in our laboratory in early stages of photoreceptor degeneration in two animal models of retinitis pigmentosa, we show that microglial cell activation is observed prior to the the initiation of photoreceptor death. We also show that there is an increase of the retinal microglial cell densities and invasion of the outer retinal layers by microglial cells. The inhibition of the microglial cells improves photoreceptor survival and morphology, documenting a role for microglial cells in photoreceptor degeneration. Furthermore, these results indicate that the modulation of microglial cell reactivity can be used to prevent or diminish photoreceptor death in inherited photoreceptor degenerations.

Abstract Inherited photoreceptor degenerations cause loss of photoreceptors and retinal remodeling which, when severe, is accompanied of retinal vessel displacements that cause retinal ganglion cell (RGC) axonal compression and death. Light‐induced photoreceptor degenerations cause similar pathologic events and ultimately RGC loss. RGC death is secondary to photoreceptor degeneration and is a delayed event that occurs in retinal sectors where there is maximal photoreceptor degeneration. Other types of acquired retinal diseases, such as taurine deficiency‐induced retinal degeneration, which may be similar to vigabatrine‐induced retinopathy, can also cause photoreceptor degeneration and RGC loss. However, in taurine deficiency, RGC loss may not be secondary to photoreceptor degeneration, but occur as an independent event and thus, RGC loss is diffuse. The combination of two treatments: taurine deficiency and light toxicity increases photoreceptor loss but not RGC loss (García‐Ayuso et al., 2018). The population of intrinsically photosensitive RGCs (ipRGCs) may respond differently than the normal population of RGCs to different types of photoreceptor degeneration because they die in similar proportions to the other RGCs in inherited photoreceptor degenerations (García‐Ayuso et al., 2015), but are selectively affected by taurine‐deficiency and may show only a temporary decrease of melanopsin expression after light‐induced damage. The investigation of RGC loss in different retinal degenerations provides us with information on the mechanisms of cell death in order to plan strategies for its prevention.