Glaucoma is a group of optic neuropathies characterised by progressive retinal ganglion cell (RGC) degeneration and is the leading cause of irreversible blindness worldwide. Current treatments for glaucoma focus on reducing intraocular pressure (IOP) with topical medications. However, many patients do not achieve sufficient IOP reductions with such treatments. Patient compliance to dosing schedules also poses a significant challenge, further limiting their effectiveness. While surgical options exist for resistant cases, these are invasive and carry risks of complications. Thus, there is a critical need for better strategies to prevent irreversible vision loss in glaucoma. Gene therapy holds significant promise in this regard, offering potential long-term solutions by targeting the disease’s underlying causes at a molecular level. Gene therapy strategies for glaucoma primarily target the two key hallmarks of the disease: elevated IOP and RGC death. This review explores key mechanisms underlying these hallmarks and discusses the current state of gene therapies targeting them. In terms of IOP reduction, this review covers strategies aimed at enhancing extracellular matrix turnover in the conventional outflow pathway, targeting fibrosis, regulating aqueous humor production, and targeting myocilin for gene-specific therapy. Neuroprotective strategies explored include targeting neurotrophic factors and their receptors, reducing oxidative stress and mitochondrial dysfunction, and preventing Wallerian degeneration. This review also briefly highlights key research priorities for advancing gene therapies for glaucoma through the clinical pipeline, such as refining delivery vectors and improving transgene regulation. Addressing these priorities will be essential for translating advancements from preclinical models into effective clinical therapies for glaucoma.

Damage-regulated autophagy modulator 2 (DRAM2) is a homologue of the DRAM family protein, which can induce autophagy process. In the retina, DRAM2 is located to the inner segment of photoreceptors, the apical surface of retinal pigment epithelial (RPE) cells, and the lysosome. Pathogenic variants of DRAM2 lead to autosomal recessive Cone-rod dystrophy 21 (CORD21). Cone-rod dystrophy is characterised by primary cone involvement, or sometimes simultaneous cone and rod loss, thus leading to decreased visual acuity, colour vision deficits, photophobia, and decreased sensitivity of the central visual field. However, the mechanisms underlying DRAM2 related retinal diseases remained unclear. To further explore the role of Dram2 in the retina, we generated Dram2 knockout mice (KO) by CRISPR/Cas-9 technology and demonstrated that expression of DRAM2 was abolished in KO retinas. Dram2 ablation failed to manifest any retinal degenerative phenotypes. Dram2 KO did not exhibit visible defect in photo response and the overt structure of the retinas. Immunostaing analysis using antibodies against cone opsins revealed no detectable loss of cone cells. Moreover, no visible change was observed in the expression and localisation of rhodopsin and other membrane disc proteins in Dram2 KO retinas and no gliosis and apoptosis were detected in KO mice. In summary, these data revealed lack of overt retinal degeneration in Dram2 KO model and emphasized the importance of further investigation of the mechanisms underlying Cone-rod dystrophy 21.

Glaucoma is a leading cause of blindness worldwide and glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs. Combining some previous published results and some new data, this paper provides our current view on how high IOP (H-IOP) affects the light response sensitivity of a subset of RGCs, the alpha-ganglion cells (αGCs), as well as their presynaptic bipolar cells (DBCs and HBCs) and A2 amacrine cells (AIIACs) in dark-adapted mouse retinas. Our data demonstrate that H-IOP in experimental glaucoma mice significantly decreases light-evoked spike response sensitivity of sONαGCs and sOFFαGCs (i.e., raises thresholds by 1.5–2.5 log units), but not that of the tONαGCs and tOFFαGCs. The sensitivity loss in sONαGCs and sOFFαGCs is mediated by a H-IOP induced suppression of AIIAC response which is caused by a decrease of transmission efficacy of the DBCR→AIIAC synapse. We also provide evidence supporting the hypothesis that BK channels in the A17AC→DBCR feedback synapse are the H-IOP sensor that regulates the DBCR→AIIAC synaptic efficacy, as BK channel blocker IBTX mimics the action of H-IOP. Our results provide useful information for designing strategies for early detection and possible treatments of glaucoma as physiological changes occur before irreversible structural damage.

The motion aftereffect (MAE) and motion adaptation in general are usually considered to be universal phenomena. However, in a preliminary study using a bias-free measure of the MAE we found some individuals who showed at best a weak effect of adaptation. These same individuals also performed poorly in a “change detection“ test of motion adaptation based on visual search, leading to the conjecture that there is a bimodality in the population with respect to motion adaptation. The present study tested this possibility by screening 102 participants on two versions of the change-detection task while also considering potential confounding factors including eye movements, practice-based improvements, and deficits in visual search ability. The 5 strongest and the 5 weakest change detectors were selected for further testing of motion detection and contrast detection after adaptation. Data showed an inverse association between change-detection ability and performance in the motion-detection task. We extend previous findings by also showing i) the weakest change detectors exhibit less direction selectivity in their contrast thresholds after adapting to drifting gratings and ii) the ability to detect change in motion direction correlates with the ability to detect change in spatial orientation. Group differences between the strongest and weakest change detectors cannot be attributed to a lack of practice, nor can they be explained by poor fixation ability. Our results suggest genuine individual differences in the degree to which adaptation is specific to stimulus orientation and direction of motion.

Viewing a rapid sequence of face images shown in the periphery can lead to large caricature-like distortions in the perceived images, a phenomenon known as the Flashed Face Distortion Effect (FFDE). The mechanisms underlying FFDE are poorly understood. Here we examined the timing and sites of the adaptation processes giving rise to the FFDE. To investigate the effects of presentation rate, we maintained consistent trial lengths while assessing how variations in the temporal frequencies of face presentation influenced the magnitude of face distortion and the averaging of facial expressions. Over a wide range of temporal frequencies (1.2–60 Hz) tested, we observed a decrease in FFDE strength as the presentation rate increased. To probe the neural sites of FFDE, we varied whether successive faces were presented to the same or different eyes using a dichoptic display. Distortion effects were comparable for monocular, binocular, and interocular conditions, yet much larger than a control condition where faces were presented with a temporal interval between successive images, suggesting a cortical locus for FFDE.

In visual foraging, foragers collect multiple items from a series of visual displays (or “patches”). When the goal is to maximize the total or the rate of collection of target items, foragers must decide when to leave a depleted patch given that “traveling” from one patch to another incurs a temporal cost. In three experiments, we investigated whether the interposition of a secondary task during travel between patches in visual foraging altered patch-leaving behavior. Over the course of 10- or 30-minute experiments, participants foraged in simulated “berry patches” and traveled to the next patch at will. While they traveled, they either actively performed a secondary task or simply observed passing visual stimuli. Travel time was varied across conditions. The addition of a secondary task, regardless of its relevance to visual foraging, to traveling, or to both, did not impact patch-leaving times in the primary visual foraging task. In Experiment 1 and more weakly in Experiment 2, the patch-leaving decision was based on how long the travel took as predicted by the Marginal Value Theorem (MVT). In Experiment 3, however, patch-leaving did not depend on travel time. Participants ‘overharvested’ in a manner that suggests that they may have adopted rules different from those of MVT. Across all three experiments, patch-leaving did not depend on the nature of the travel.

The receptive field (RF) is the fundamental processing unit of human vision; both masking and crowding depend on its size. The RF has a psychophysical corresponding term, the perceptive field (PF); whereas the RF is measured physiologically, the PF is measured psychophysically (a perceptual response). We investigated how spatial (lateral interactions), temporal (the stimulus presentation time), and the procedure affect the PF size for both monocular and binocular viewing. The stimuli consisted of a central vertically oriented Gabor target and high-contrast Gabor flankers positioned in two configurations (orthogonal or collinear) with target-flanker separations of either 2 or 3 wavelengths (λ). We used two main methods to control the monocular and binocular vision: mono-optic glasses vs. stereo glasses. The presentation order was either mixed or non-mixed for the presentation time and the eye condition. We estimated the PF size for both monocular and binocular viewing at 4 different presentation times (40, 80,120, and 200 ms) with different orders of presentation in each experiment (mono-optic glasses vs. stereo glasses, utilizing the lateral masking paradigm). In each experiment we explored one variable: how changing one parameter would affect the PF size in both monocular and binocular viewing (the temporal duration, the testing order of conditions, and the spatial distance) while keeping the others constant. We found that both the monocular and binocular PF size were dynamic and were significantly affected by the presentation order, leading to reduced lateral suppression under the collinear 2λ condition. Hence, both the monocular and binocular PF size depended on the sequence of the stimulus presentation time and the testing order of the conditions. Furthermore, we found that the binocular PF size was significantly larger than the monocular PF size.

A quintessential sentinel of cell health, the membrane potential in nonexcitable cells integrates biochemical and biomechanical inputs, determines the driving force for ionic currents activated by input signals and plays critical functions in cellular differentiation, signaling, and pathology. The identity and properties of ion channels that subserve the resting potential in trabecular meshwork (TM) cells is poorly understood, which impairs our understanding of intraocular pressure regulation in healthy and diseased eyes. Here, we identified a powerful cationic conductance that subserves the TM resting potential. It disappears following Na+ removal or substitution with choline or NMDG+, is insensitive to TTX, verapamil, phenamil methanesulfonate, amiloride and GsMTx4, is substituted by Li+ and Cs+, and inhibited by Gd3+ and Ruthenium Red. Constitutive cation influx is thus not mediated by voltage-operated Na+, Ca2+, epithelial Na+ (ENaC) channels, Piezo channels or Na+/H+ exchange but may involve TRP-like channels. Transcriptional analysis detected expression of many TRP genes, with the transcriptome pool dominated by TRPC1 followed by expression of TRPV1, TRPC3, TRPV4 and TRPC5. Pyr3 and Pico1,4,5 did not affect the standing current whereas SKF96365 promoted rather than suppressed, Na+ influx. SEA-0400 induced a modest hyperpolarization, indicating residual contribution from Na+/Ca2+ exchange. The resting membrane potential in human TM cells is thus maintained by a constitutive monovalent cation leak current with properties not unlike those of TRP channels. This conductance is likely to influence conventional outflow by setting the homeostatic steady-state and by regulating the magnitude of pressure-induced currents in normotensive and hypertensive eyes.