The survival and function of retinal neurons is dependent on mitochondrial energy generation and its intracellular distribution by creatine kinase. Post ischemic disruption of retinal creatine synthesis, creatine kinase activity, or transport of creatine into neurons may impair retinal function. S-adenosyl-l-methionine (SAMe) is required for creatine synthesis, phosphatidylcholine and glutathione synthesis, and transducin methylation. These reactions are essential for photoreceptor function but may be downregulated after ischemia due to a reduction in SAMe. Our aim was to determine whether administration of SAMe after ischemia could improve retinal function. Unilateral retinal ischemia was induced in adult rats by increasing the intraocular pressure to 110 mm Hg for 60 min. Immediately after the ischemic insult, SAMe was injected into the vitreous (100 μm), followed by oral administration (69 mg/kg/day) for 5 or 10 days. Retinal function (electroretinography), histology, and creatine transporter (CRT-1) expression were analyzed. Photoreceptoral responses (RmP3, S), rod and cone bipolar cell responses (PII), and oscillatory potentials were reduced by the ischemia/reperfusion insult. Although SAMe treatment ameliorated the ischemia-induced histological damage by day 5, there was no improvement in retinal function and the intensity of CRT-1 labeling in ischemic retinas was markedly reduced. However, 10 days after ischemia, a recovery in CRT-1 immunolabeling was evident and SAMe supplementation significantly restored photoreceptor function and rod PII responses. In conclusion, these data suggest that creatine transport and methylation reactions, such as creatine synthesis, may be compromised by an ischemic insult contributing to retinal dysfunction and injury. Oral SAMe supplementation after retinal ischemia may provide an effective, safe, and accessible neuroprotective strategy.

The Ras-like Rab1 and Rab6 GTPases modulate protein traffic along the early secretory pathway and are involved in the regulation of maturation of rhodopsin in the outer retina. However, Rab GTPases have not been studied in the inner retinas. Here, we analyzed the anatomatic distribution and expression of Rab1 and Rab6 in the mouse and rat retinas by immunohistochemistry and immunoblotting. We found that Rab1 was specifically expressed in the rod bipolar cells, while Rab6 was expressed in a different cell type(s) from rod bipolar cells in the inner retina. We also demonstrated that expression of Rab1 and Rab6 was increased with light. These data provided the first evidence implicating that Rab1 and Rab6 may be involved in the regulation of the retinal adaptation.

A DBA/2J (D2) transgenic mouse line with cyan fluorescent protein (CFP) reporter expression in ganglion cells was developed for the analysis of ganglion cells during progressive glaucoma. The Thy1-CFP D2 (CFP-D2) line was created by congenically breeding the D2 line, which develops pigmentary glaucoma, and the Thy1-CFP line, which expresses CFP in ganglion cells. Microsatellite marker analysis of CFP-D2 progeny verified the genetic inclusion of the D2 isa and ipd loci. Specific mutations within these loci lead to dysfunctional melanosomal proteins and glaucomatous phenotype in D2 mice. Polymerase chain reaction analysis confirmed the inclusion of the Thy1-CFP transgene. CFP-fluorescent ganglion cells, 6–20 μm in diameter, were distributed in all retinal regions, CFP processes were throughout the inner plexiform layer, and CFP-fluorescent axons were in the fiber layer and optic nerve head. Immunohistochemistry with antibodies to ganglion cell markers NF-L, NeuN, Brn3a, and SMI32 was used to confirm CFP expression in ganglion cells. Immunohistochemistry with antibodies to amacrine cell markers HPC-1 and ChAT was used to confirm weak CFP expression in cholinergic amacrine cells. CFP-D2 mice developed a glaucomatous phenotype, including iris disease, ganglion cell loss, attrition of the fiber layer, and elevated intraocular pressure. A CFP-D2 transgenic line with CFP-expressing ganglion cells was developed, which has (1) a predominantly D2 genetic background, (2) CFP-expressing ganglion cells, and (3) age-related progressive glaucoma. This line will be of value for experimental studies investigating ganglion cells and their axons in vivo and in vitro during the progressive development of glaucoma.

The chicken has been extensively studied as an animal model for myopia because its eye growth is tightly controlled by visual experience. It has been found that the retina controls the axial eye growth rates depending on the amount and the sign of defocus imposed in the projected image. Glucagonergic amacrine cells were discovered that appear to encode for the sign of imposed defocus. It is not clear whether the downstream neurons, the retinal ganglion cells, still have access to this information—and whether it ultimately reaches the brain. We have analyzed the spike rates of chicken retinal ganglion cells in vitro using a microelectrode array. For this purpose, we initially defined spatial resolution and contrast sensitivity in vitro. Two classes of chicken retinal ganglions were found, depending on the linearity of their responses with increasing contrast. Responses generally declined with increasing defocus of the visual stimulus. These responses were well predicted by the modulation transfer function for a diffraction-limited defocused optical system, the first Bessel function. Thus, the studied retinal ganglion cells did not distinguish between a loss of contrast at a given spatial frequency due to reduced contrast of the stimulus pattern or because the pattern was presented out of focus. Furthermore, there was no indication that the retinal ganglion cells responded differently to defocus of either sign, at least for the cells that were recorded in this study.

We investigated the effect of auditory–visual sensory integration on visual tasks that were predominantly dependent on parvocellular processing. These tasks were (i) detecting metacontrast-masked targets and (ii) discriminating orientation differences between high spatial frequency Gabor patch stimuli. Sounds that contained no information relevant to either task were presented before, synchronized with, or after the visual targets, and the results were compared to conditions with no sound. Both tasks used a two-alternative forced choice technique. For detecting metacontrast-masked targets, one interval contained the visual target and both (or neither) intervals contained a sound. Sound–target synchrony within 50 ms lowered luminance thresholds for detecting the presence of a target compared to when no sound occurred or when sound onset preceded target onset. Threshold angles for discriminating the orientation of a Gabor patch consistently increased in the presence of a sound. These results are compatible with sound-induced activity in the parvocellular visual pathway increasing the visibility of flashed targets and hindering orientation discrimination.

The aim of this study was to explore the plasticity of fixation in patients with central vision loss. Most of these patients use preferred retinal loci (PRLs) in the healthy eccentric part of the retina to fixate, but fixation stability and retinal location are not always optimal for best visual performance. This study examined whether fixation stability and a new PRL location can be trained and whether these changes in ocular motor control transfer into better reading performance. Six patients with age-related macular degeneration participated in the study. Fixation stability measurements, microperimetry, and auditory biofeedback training were performed with the MP-1 microperimeter. The auditory biofeedback was used during five 1-h long training sessions to improve fixation and relocate the PRL. Fixation location and stability were recorded while viewing four different targets: a cross, a letter, a word, and a nine-cycle radial grating. Visual acuity was assessed with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart and reading performance with the MNRead test. The results showed that all patients developed a new PRL in an optimal location for reading, and they were able to use it consistently while viewing different targets. Fixation stability improved 53% after training. Learning transferred to the old PRL even though fixation stability at this location was not trained. All these improvements in ocular motor control translated into better reading performance: reading speed improved 38% and reading acuity and critical print size gained two lines. We conclude that the ability of the ocular motor system to fixate is flexible in patients with central vision loss: a new PRL can be trained, fixation stability can be improved, and learning transfers to an untrained location. These gains in ocular motor control result in better visual performance. This property can be successfully used to optimize the residual vision of patients with central vision loss.

The retina displays numerous processes that follow a circadian rhythm. These processes are coordinated through the direct action of light on photoreceptive molecules and, in the absence of light, through autocrine/paracrine actions of extracellular neuromodulators. We previously described the expression of the genes encoding the secreted heparin-binding growth factors, midkine-a (mdka) and midkine-b (mdkb), in the retina of the zebrafish. Here, we provide evidence that the expression of mdka and mdkb follows a daily rhythm, which is independent of the presence or absence of light, and we propose that the expression of mdka is regulated by the circadian clock. Both qualitative and quantitative measures show that for mdka, the levels of mRNA and protein decrease during the night and increase during the subjective day. Qualitative measures show that the expression of mdkb increases during the second half of the subjective night and decreases during the second half of the subjective day. Within horizontal cells, the two midkine paralogs show asynchronous circadian regulation. Though intensely studied in the contexts of physiology and disease, this is the first study to provide evidence for the circadian regulation of midkines in the vertebrate nervous system.