In the retina, melatonin is secreted at night by rod/cone photoreceptors and serves as a dark-adaptive signal. Melatonin receptors have been found in many retinal neurons including melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting it could modulate the physiology of these inner retinal photoreceptors. Here, we investigated whether melatonin modulates the alpha-like M4-type ipRGCs, which are believed to mediate image-forming vision as well as non-image-forming photoresponses. Applying melatonin during daytime (when endogenous melatonin secretion is low) caused whole-cell-recorded M4 cells' rod/cone-driven depolarizing photoresponses to become broader and larger, whereas the associated elevation in spike rate was reduced. Melanopsin-based light responses were not affected significantly. Nighttime application of the melatonin receptor antagonist luzindole also altered M4 cells' rod/cone-driven light responses but in the opposite ways: the duration and amplitude of the graded depolarization were reduced, whereas the accompanying spiking increase was enhanced. These luzindole-induced changes confirmed that M4 cells are modulated by endogenous melatonin. Melatonin could induce the above effects by acting directly on M4 cells because immunohistochemistry detected MT1 receptors in these cells, although it could also act presynaptically. Interestingly, the daytime and nighttime recordings showed significant differences in resting membrane potential, spontaneous spike rate and rod/cone-driven light responses, suggesting that M4 cells are under circadian control. This is the first report of a circadian variation in ipRGCs' resting properties and synaptic input, and of melatoninergic modulation of ipRGCs.
Rhodopsin phosphorylation was investigated using synthetic C-terminal peptides from rhodopsin. The peptides were phosphorylated by expressed rhodopsin kinase (RK) in the presence of a photolyzed truncated rhodopsin at the C-terminus. No peptide phosphorylation was detected under dark or in conditions in which RK was inactive. However, the phosphorylation rate was significantly higher in the following three peptides: (345M Rho, 330DDEASTTVSKTETSQMAPA; 347S Rho, 330DDEASTTVSKTETSQVASA; and 347L Rho: 330DDEASTTVSKTETSQVALA) taken from missense mutations of rhodopsin found in patients with autosomal retinitis pigmentosa (ADRP) as compared with that from wild-type rhodopsin (330DDEASTTVSKTETSQVAPA). Distribution of the phosphorylation showed a similar ratio among three serines (334, 338 and 343) in 347L Rho mutation to wild type. However, 345M Rho and 347S Rho peptides showed higher phosphorylation at Ser334. The data obtained suggests that an abnormally high rate of phosphorylation in missense mutations around the rhodopsin C-terminus may change the position of phosphorylation and inactivation process of the visual transduction.
Most eyes start with a hypermetropic refractive error at birth, but the growth rates of the ocular components, guided by visual cues, will slow in such a way that this refractive error decreases during the first 2 years of life. Once reaching its target, the eye enters a period of stable refractive error as it continues to grow by balancing the loss in corneal and lens power with the axial elongation. Although these basic ideas were first proposed over a century ago by Straub, the exact details on the controlling mechanism and the growth process remained elusive. Thanks to the observations collected in the last 40 years in both animals and humans, we are now beginning to get an understanding how environmental and behavioral factors stabilize or disrupt ocular growth. We survey these efforts to present what is currently known regarding the regulation of ocular growth rates.
The arthropod compound eye represents one of two major eye types in the animal kingdom and has served as an essential experimental paradigm for defining fundamental mechanisms underlying sensory organ formation, function, and maintenance. One of the most distinguishing features of the compound eye is the highly regular array of lens facets that define individual eye (ommatidial) units. These lens facets are produced by a deeply conserved quartet of cuticle-secreting cells, called Semper cells (SCs). Also widely known as cone cells, SCs were originally identified for their secretion of the dioptric system, i.e. the corneal lens and underlying crystalline cones. Additionally, SCs are now known to execute a diversity of patterning and glial functions in compound eye development and maintenance. Here, we present an integrated account of our current knowledge of SC multifunctionality in the Drosophila compound eye, highlighting emerging gene regulatory modules that may drive the diverse roles for these cells. Drawing comparisons with other deeply conserved retinal glia in the vertebrate single lens eye, this discussion speaks to glial cell origins and opens new avenues for understanding sensory system support programs.
The central role of the cardiovascular system is to maintain adequate capillary perfusion. The spatially and temporally heterogeneous nature of capillary perfusion has been reported in some organs. However, such heterogeneous perfusion properties have not been sufficiently explored in the retina. Arguably, spatial and temporal heterogeneity of capillary perfusion could be more predominant in the retina than that in other organs. This is because the retina is one of the highest metabolic demand neural tissues yet it has a limited blood supply due to optical requirements. In addition, the unique heterogeneous distribution of retinal neural cells within different layers and regions, and the significant heterogeneity of intraretinal oxygen distribution and consumption add to the complexity. Retinal blood flow distribution must match consumption of nutrients such as oxygen and glucose within the retina at the cellular level in order to effectively maintain cell survival and function. Sophisticated local blood flow control in the microcirculation is likely required to control the retinal capillary perfusion to supply local retinal tissue and accommodate temporal and spatial variations in metabolic supply and demand.The authors would like to update the knowledge of the retinal microvessel and capillary network and retinal oxidative metabolism from their own studies and the work of others. The coupling between blood supply and energy demands in the retina is particularly interesting. We will mostly describe information regarding the retinal microvessel network and retinal oxidative metabolism relevant to the spatial and temporal heterogeneity of capillary perfusion. We believe that there is significant and necessary spatial and temporal heterogeneity and active regulation of retinal blood flow in the retina, particularly in the macular region.Recently, retinal optical coherence tomography angiography (OCTA) has been widely used in ophthalmology, both experimentally and clinically. OCTA could be a valuable tool for examining retinal microvessel and capillary network structurally and has potential for determining retinal capillary perfusion and its control. We have demonstrated spatial and temporal heterogeneity of capillary perfusion in the retina both experimentally and clinically. We have also found close relationships between the smallest arterioles and capillaries within paired arterioles and venules and determined the distribution of smooth muscle cell contraction proteins in these vessels. Spatial and temporal heterogeneity of retinal capillary perfusion could be a useful parameter to determine retinal microvessel regulatory capability as an early assay for retinal vascular diseases.This topic will be of great interest, not only for the eye but also other organs. The retina could be the best model for such investigations. Unlike cerebral vessels, retinal vessels can be seen even at the capillary level. The purpose of this manuscript is to share our current understanding with the readers and encourage more researchers and clinicians to investigate this field. We begin by reviewing the general principles of microcirculation properties and the spatial and temporal heterogeneity of the capillary perfusion in other organs, before considering the special requirements of the retina. The local heterogeneity of oxygen supply and demand in the retina and the need to have a limited and well-regulated retinal circulation to preserve the transparency of the retina is discussed. We then consider how such a delicate balance of metabolic supply and consumption is achieved. Finally we discuss how new imaging methodologies such as optical coherence tomography angiography may be able to detect the presence of spatial and temporal heterogeneity of capillary perfusion in a clinical setting. We also provide some new information of the control role of very small arterioles in the modulation of retinal capillary perfusion which could be an interesting topic for further investigation.
Retinal degenerations are typically characterized by loss of highly differentiated cells within the neurosensory retina, such as photoreceptors, or retinal pigment epithelium (RPE). RPE loss is the final common pathway in a number of degenerations including the leading cause of new blindness in the developed world: age-related macular degeneration. Targeting the RPE for transplantation with stem cell derived tissue presents a reasonable therapeutic opportunity in a variety of important, otherwise untreatable, blinding conditions. This chapter presents the pathophysiologic case for this strategy, the preclinical data substantiating the hypothesis, and the initial clinical trials safety data from early human trials.
Following partial loss of photoreceptor cells in the retina of mice afflicted by mutant genes, damaging light exposure, or old age, some of the remaining rod cells exhibited a process of growth in their synapses with the second order retinal neurons. This growth was recognized by the presence of multiple synaptic sites in some of the rod terminals in the outer plexiform layer. In this study, a comparative analysis of the microanatomical changes in the synaptic structures of the rod terminals in the retina of normal, rds homozygous and heterozygous mutant and light exposed albino mice was undertaken by using a computer-aided three-dimensional reconstruction. A rod terminal normally showed the presence of 1 synaptic complex consisting of a single synaptic ribbon located between 2 processes of horizontal cells and 2 bipolar cell dendrites. In a rod terminal showing an enlarged synaptic complex, 2 or 3 separate synaptic ribbons formed the centres of separate synaptic sites; each of the sites was characterized by the presence of 2 laterally placed horizontal cell processes and 2 bipolar cell dendrites. However, these processes from the multiple synaptic sites were observed to arise from the 2 horizontal and the 2 bipolar cell elements that were normally present in the rod terminal. Thus proliferation of synaptic sites in the rod terminals occurred through growth and sprouting from the processes of the second order neuronal components present within the terminals. The altered synaptic complexes in the variously affected groups were structurally comparable and appeared to have resulted from similar microanatomical changes. The increase in the frequency of rod terminals with multiple synaptic sites occurred as a sequel to increasing photoreceptor cell loss that was recorded at different age points in the different experimental groups. It is concluded that rod synapses in the adult mammalian retina possess structural plasticity that permits compensatory growth.
4. Photoreceptor Function and Susceptibility to Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 4.
The light-sensing rod photoreceptor cell exhibits several adaptations in response to the lighting environment. While adaptations to short-term changes in lighting conditions have been examined in depth, adaptations to long-term changes in lighting conditions are less understood. Atomic force microscopy was used to characterize the structure of rod outer segment disc membranes, the site of photon absorption by the pigment rhodopsin, to better understand how photoreceptor cells respond to long-term lighting changes. Structural properties of the disc membrane changed in response to housing mice in constant dark or light conditions and these adaptive changes required output from the phototransduction cascade initiated by rhodopsin. Among these were changes in the packing density of rhodopsin in the membrane, which was independent of rhodopsin synthesis and specifically affected scotopic visual function as assessed by electroretinography. Studies here support the concept of photostasis, which maintains optimal photoreceptor cell function with implications in retinal degenerations.
From the retina of the land-locked population of the sea lamprey, Petromyzon marinus, a photolabile pigment was extracted which was identified spectrophotometrically as a member of the rhodopsin group of pigments. Using the absorption spectrum of a relatively pure solution and analysis by means of difference spectra, the peak of this pigment was placed at about 497 mmicro. The method of selective bleaching by light of different wave lengths revealed no significant amounts of any other pigment in the extracts. A similar pigment was also detected in retinal extracts of the Pacific Coast lamprey, Entospenus tridentatus. These results are significant for two reasons: (a) the lamprey is shown to be an example of an animal which spawns in fresh water but which is characterized by the presence of rhodopsin, rather than porphyropsin, in the retina; (b) the primitive phylogenetic position of the lamprey suggests that rhodopsin was the visual pigment of the original vertebrates.
