In retinitis pigmentosa (RP), one of many possible genetic mutations causes rod degeneration, followed by cone secondary death leading to blindness. Accumulating evidence indicates that rod death triggers multiple, non-cell-autonomous processes, which include oxidative stress and inflammation/immune responses, all contributing to cone demise. Inflammation relies on local microglia and recruitment of immune cells, reaching the retina through breakdowns of the inner blood retinal barrier (iBRB). Leakage in the inner retina vasculature suggests similarly altered outer BRB, formed by junctions between retinal pigment epithelium (RPE) cells, which are crucial for retinal homeostasis, immune response, and privilege. We investigated the RPE structural integrity in three models of RP (rd9, rd10, and Tvrm4 mice) by immunostaining for zonula occludens-1 (ZO-1), an essential regulatory component of tight junctions. Quantitative image analysis demonstrated discontinuities in ZO-1 profiles in all mutants, despite different degrees of photoreceptor loss. ZO-1 interruption zones corresponded to leakage of in vivo administered, fluorescent dextran through the choroid-RPE interface, demonstrating barrier dysfunction. Dexamethasone, administered to rd10 mice for rescuing cones, also rescued RPE structure. Thus, previously undetected, stereotyped abnormalities occur in the RPE of RP mice; pharmacological targeting of inflammation supports a feedback loop leading to simultaneous protection of cones and the RPE.

Brain plasticity is a well-established concept designating the ability of central nervous system (CNS) neurons to rearrange as a result of learning, when adapting to changeable environmental conditions or else while reacting to injurious factors. As a part of the CNS, the retina has been repeatedly probed for its possible ability to respond plastically to a variably altered environment or to pathological insults. However, numerous studies support the conclusion that the retina, outside the developmental stage, is endowed with only limited plasticity, exhibiting, instead, a remarkable ability to maintain a stable architectural and functional organization. Reviewed here are representative examples of hippocampal and cortical paradigms of plasticity and of retinal structural rearrangements found in organization and circuitry following altered developmental conditions or occurrence of genetic diseases leading to neuronal degeneration. The variable rate of plastic changes found in mammalian retinal neurons in different circumstances is discussed, focusing on structural plasticity. The likely adaptive value of maintaining a low level of plasticity in an organ subserving a sensory modality that is dominant for the human species and that requires elevated fidelity is discussed.

Retinal pigment epithelium (RPE) is a specialized pigmented monolayer dedicated to retinal support and protection. Given the fact that photoreceptor outer segments are the primary energy resource of RPE metabolism, it follows that, when photoreceptor function is compromised, RPE cells are impaired and vice versa. In retinitis pigmentosa (RP), genetic mutations lead to a massive degeneration of photoreceptors but only few studies have addressed systematically the consequences of rod and cone death on RPE cells, which, among others, undergo an abnormal organization of tight junctions (TJs) and a compromised barrier function. The biological mechanisms driving these barrier reorganizations are largely unknown. Studies aimed at addressing general and mutation‐independent changes of the RPE in RP are relevant to reveal new pathogenic mechanisms of this heterogeneous family of diseases and prospectively develop effective therapeutic strategies. Here, we take advantage of a mouse model of RP in which retinal degeneration is spatially restricted to investigate a possible involvement of inflammatory responses in RPE remodeling. By immunostaining for Zona Occludens‐1 (ZO‐1), a structural and functional marker of TJs with pleiotropic functions, we found a partial rescue of TJs organization following local restoration of retinal organization, revealing that TJs structure can recover. Since lack of ZO‐1 from TJs can alter cell density, we counted RPE cells without finding any differences between degenerated and controls animals, indicating preservation of RPE cells. However, we found an increased number of immune cells adhering to the RPE apical surface and a spatial correlation with areas of abnormal ZO‐1 distribution. This suggests that inflammatory processes following photoreceptor degeneration can be responsible for TJs alterations during RP progression and deserve further investigation.

Retinitis pigmentosa (RP) is a family of genetically heterogeneous diseases still without a cure. Despite the causative genetic mutation typically not expressed in cone photoreceptors, these cells inevitably degenerate following the primary death of rods, causing blindness. The reasons for the “bystander” degeneration of cones are presently unknown but decrement of survival factors, oxidative stress, and inflammation all play a role. Targeting these generalized biological processes represents a strategy to develop mutation-agnostic therapies for saving vision in large populations of RP individuals. A classical method to support neuronal survival is by employing neurotrophic factors, such as NGF. This study uses painless human NGF (hNGFp), a TrkA receptor-biased variant of the native molecule with lower affinity for nociceptors and limited activity as a pain inducer; the molecule has identical neurotrophic power of the native form but a reduced affinity for the p75NTR receptors, known to trigger apoptosis. hNGFp has a recognized activity on brain microglial cells, which are induced to a phenotype switch from a highly activated to a more homeostatic configuration. hNGFp was administered to RP-like mice in vivo with the aim of decreasing retinal inflammation and also providing retinal neuroprotection. However, the ability of this treatment to counteract the bystander degeneration of cones remained limited.