Retinal Ganglion Cell Density Research Articles

Convolutional neural networks develop major organizational principles of early visual cortex when enhanced with retinal sampling.

Primate visual cortex exhibits key organizational principles: cortical magnification, eccentricity-dependent receptive field size and spatial frequency tuning as well as radial bias. We provide compelling evidence that these principles arise from the interplay of the non-uniform distribution of retinal ganglion cells, and a quasi-uniform convergence rate from the retina to the cortex. We show that convolutional neural networks outfitted with a retinal sampling layer, which resamples images according to retinal ganglion cell density, develop these organizational principles. Surprisingly, our results indicate that radial bias is spatial-frequency dependent and only manifests for high spatial frequencies. For low spatial frequencies, the bias shifts towards orthogonal orientations. These findings introduce a novel hypothesis about the origin of radial bias. Quasi-uniform convergence limits the range of spatial frequencies (in retinal space) that can be resolved, while retinal sampling determines the spatial frequency content throughout the retina.

TRPV4 antagonist suppresses retinal ganglion cell apoptosis by regulating the activation of CaMKII and TNF-α expression in a chronic ocular hypertension rat model

Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs), leading to irreversible visual function impairment. Sustained increase in intraocular pressure represents a major risk factor for glaucoma, yet the underlying mechanisms of RGC apoptosis induced by intraocular pressure remains unclear. This study aims to investigate the role of TRPV4 in RGC apoptosis in a rat model of chronic ocular hypertension (COH) and the underlying molecular mechanism. In the COH rat models, we evaluated the visual function, retinal pathological changes and RGC apoptosis. TRPV4 expression and downstream signaling molecules were also detected. We found that RGC density decreased and RGC apoptosis was induced in COH eyes compared with control eyes. TRPV4 expression increased significantly in response to elevated IOP. TRPV4 inhibition by the TRPV4 antagonist HC-067047 (HC-067) suppressed RGC apoptosis and protected visual function. HC-067 treatment upregulated the phosphorylation of CaMKII in both control and COH eyes. Finally, HC-067 treatment suppressed the production of TNF-α induced by ocular hypertension. The TRPV4 antagonist HC-067 might suppress RGC apoptosis by regulating the activation of CaMKII and inhibiting the production of TNF-α in the COH model. This indicated that TRPV4 antagonists may be a potential and novel therapeutic strategy for glaucoma.

Retinal ganglion cell and microvascular density loss in hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is characterized by progressive degeneration of distal axons in the long corticospinal tracts. Loss of retinal cells and microvascular networks has neither been suspected nor investigated. We concurrently examined the retinal microvasculature and retinal layer morphology in patients with HSP to assess whether retinal features may portray disease and its progression. Fifteen patients with HSP and 30 healthy controls were included in this cross-sectional case-control study. Disease severity was assessed with the Spastic Paraplegia Rating Scale (SPRS). Severity of ataxia was determined by the Scale for the Assessment and Rating of Ataxia (SARA). Retinal microvasculature was measured by means of optical coherence tomography angiography (OCT-A) and morphology of retinal layers using structural OCT. Mixed-effects models were applied for data analysis. HSP patients showed significantly reduced vessel density of the superficial vascular plexus (SVP), reduced ganglion cell layer (GCL) volume, reduced inner plexiform layer (IPL) volume and reduced temporal-inferior peripapillary retinal nerve fiber layer (pRNFL) thickness versus healthy controls. GCL volume reduction correlated significantly with the worsening of visual acuity and higher SARA scores. These findings demonstrate that, in HSP both cells and vascular networks of the retina are compromised. Assessment of the retinal GCL, IPL and SVP may aid in diagnosis and monitoring of disease progression as well as provide novel structural outcome measures for clinical trials.

COENZYME Q10 EFFECT ON NMDA RECEPTOR EXPRESSION AND RETINAL GANGLION CELL DENSITY (Experimental Study in Traumatic Optic Neuropathy Model of Wistar Rat)

Abstract
 Introduction & Objectives : Traumatic optic neuropathy is a visual disturbance condition after acute injury to optic nerve. This injury results in retinal ganglion cells ischemic leading to excitotoxicity and apoptosis. Coenzyme Q10 (CoQ10) is an antioxidant and cofactor in electron transport within mitochondria that inhibits glutamate excitotoxicity and thereby preventing retinal ganglion cell apoptosis. This research aims to prove the effect of coenzyme Q10 on NMDA receptor expression and retinal ganglion cell density in rat model of traumatic optic neuropathy.
 Methods : This study use post-test only randomized controlled groups design. Traumatic optic neuropathy wistar rats model was made by optic nerve crushed method, then given oral CoQ10 100mg/kgBW after 1 hour for 14 days in treatment group. Retinal histopathological specimen was made with immunohistochemistry and Haematoxyllin-eosin staining and examined under microscope with 400x magnification. Data was verified and statistically analyzed.
 Results : The NMDA receptor expression in the treatment group was significantly lower than control (p=0.009). The retinal ganglion cell density in the treatment group was significantly higher than control (p=0.009). There was a significant correlation between NMDA receptor expression and retinal ganglion cell density in the treatment group (p = 0.012) with a strong negative correlation direction (r = - 0.652).
 Conclusion : Administration of CoQ10 in traumatic optic neuropathy model rats affects NMDA receptor expression and retinal ganglion cell density. NMDA receptor expression was lower with higher retinal ganglion cell density in the treatment group. NMDA receptor expression was inversely proportional to retinal ganglion cell density in the treatment group.

EFFECT OF TOPICAL BRIMONIDINE ON NMDA RECEPTOR EXPRESSION AND RETINA GANGLION CELL DENSITY IN TRAUMATIC OPTIC NEUROPATHY RATS MODEL

Abstract
 Introduction & Objectives : Traumatic optic neuropathy is a visual disturbance caused by acute injury to the optic nerve which results in retinal ganglion cell apoptosis through the glutamate excitotoxicity pathway. Brimonidine is an alpha 2-receptor agonist that acts as a neuroprotector in the glutamate excitotoxicity pathway and causes modulation of NMDA receptors associated with glutamate. Objective of this study is to prove the effect of topical brimonidine on NMDA receptor expression and retinal ganglion cell density in a rat model of traumatic optic neuropathy
 Methods : Rat models of traumatic optic neuropathy was carried out using the optic nerve crush method. The treatment group was given topical brimonidine 0.15% 1 drop/12 hours for 14 days. NMDA receptor expression was assessed by immunohistochemical staining and retinal ganglion cell density was assessed by Hematoxylin-eosin staining. Statistical analysis was performed to assess the correlation between NMDA receptor expression and retinal ganglion cell density
 Results : The Allred score of NMDA receptors expression in the treatment group was lower than control group, with significant difference (p=0.002). The mean density of retinal ganglion cells in the treatment and control group was 20,99  7,76 and 12,51  3,10, respectively with a significant difference (p=0.032). There was a significant correlation between NMDA receptor expression and retinal ganglion cell density in the treatment group (p=0.035) with strong negative correlation (r= -0.611)
 Conclusion : Topical administration of brimonidine to the Wistar rat model of traumatic optic neuropathy can suppress NMDA receptor expression and maintain retinal cell ganglion density

EFFECT OF ORAL CURCUMIN ADMINISTRATION ON NMDA RECEPTOR EXPRESSION AND RETINAL GANGLION CELL DENSITY

Abstract
 Introduction & Objectives : To prove the effect of oral curcumin on NMDA receptor expression and retinal ganglion cell density.
 Methods : Wistar rats model of traumatic optic neuropathy were divided into 2 groups. The treatment group was given oral curcumin 150mg/kgBW/24 hours for 14 days 1 hour after trauma. NMDA receptor expression was examined by IHC staining and retinal ganglion cell density was examined by HE staining. Data were collected and analyzed.
 Results : NMDA expression was found to be significantly lower in the treatment group compared to the control group (p = 0.046). The mean of ganglion density in the control and treatment group was 12.88 ± 2.44 and 17.92 ± 6.95, respectively. The treatment group had a significantly higher ganglion density (p = 0.043). There was a significant relationship between NMDA receptor expression and retinal ganglion density (p = 0.043, r = -0.591).
 Conclusion : Curcumin can suppress the expression of NMDA receptors to maintain retinal ganglion density in rat models of optic neuropathy

Transsynaptic Degeneration of Retinal Ganglion Cells Following Lesions to Primary Visual Cortex in Marmosets.

A lesion to primary visual cortex (V1) in primates can produce retrograde transneuronal degeneration in the dorsal lateral geniculate nucleus (LGN) and retina. We investigated the effect of age at time of lesion on LGN volume and retinal ganglion cell (RGC) density in marmoset monkeys. Retinas and LGNs were obtained about 2years after a unilateral left-sided V1 lesion as infants (n = 7) or young adult (n = 1). Antibodies against RBPMS were used to label all RGCs, and antibodies against CaMKII or GABAA receptors were used to label nonmidget RGCs. Cell densities were compared in the left and right hemiretina of each eye. The LGNs were stained with the nuclear marker NeuN or for Nissl substance. In three animals lesioned within the first 2 postnatal weeks, the proportion of RGCs lost within 5mm of the fovea was ∼twofold higher than after lesions at 4 or 6 weeks. There was negligible loss in the animal lesioned at 2years of age. A positive correlation between RGC loss and LGN volume reduction was evident. No loss of CaMKII-positive or GABAA receptor-positive RGCs was apparent within 2mm of the fovea in any of the retinas investigated. Susceptibility of marmoset RGCs to transneuronal degeneration is high at birth and declines over the first 6 postnatal weeks. High survival rates of CaMKII and GABAA receptor-positive RGCs implies that widefield and parasol cells are less affected by neonatal cortical lesions than are midget-pathway cells.

Retinal microglia and ganglion cells in a cuprizone (CPZ) induced mouse model of multiple sclerosis (MS)

Aims/Purpose: Up to 90% of MS patients have ocular manifestations. Activated microglia (mg) are associated with age and diseases like MS. Mg change their activation states (ramified, hyper‐ramified, activated, amoeboid and rod) in response to stimuli, to exert either neuro‐protective or ‐toxic effects, leading to the rescue or loss of neurons. Here, we characterize retinal ganglion cell (RGC) densities and retinal mg morphotype proportions in eyes of a CPZ induced MS model and age‐matched controls.Methods: Male C57 mice were fed CPZ (0.2%w/w) mixed chow for 4 months (m) until sacrificed at 6 m (6mCPZ) or 28 m (28mCPZ) old. Age‐matched controls (6mCtrl; 28mCtrl) were fed normal chow. Enucleated eyes were fixed in 4% PFA. Whole retinas were dissected, stained (RBPMS+RGCs; iba‐1+mg), mounted and imaged. A published retinal mg morphotyping algorithm and an automated RBPMS counting script were used. Two‐way ANOVA with paired analysis (PA) was used (mg n: 6mCtrl = 15; 6mCPZ = 7; 28mCtrl = 7; 28mCPZ = 10; and RGC n: 6mCtrl = 4; 6mCPZ = 3; 28mCtrl = 3; 28mCPZ = 4).Results: There was a main effect of age for activated (p = 0.0282) and rod (p < 0.0001), and disease state for rod (p = 0.04) mg. PA showed higher activated mg in 28mCtrl versus 6mCtrl (p = 0.0485), and lower rod mg in 28mCtrl versus 6mCtrl (p = 0.0374) and in 28mCPZ versus 6mCPZ (p = 0.0007). There was a main effect of age (p = 0.0001) and disease state (p = 0.04) on RBPMS density. PA showed lower RGC density in 28mCtrl versus 6mCtrl (p = 0.0025) and in 28mCPZ versus 6mCPZ (p = 0.025).Conclusions: Our results show that there is age‐related loss of rod mg and RGCs in healthy and CPZ groups, supporting reports that rod mg are involved in protecting less damaged neurons. Age‐related increased activated mg may cause RGC loss as transcription factors like TNFα, bind to RGC receptors, inducing apoptosis. Further transcriptomic analysis may clarify functional interpretations.

Increasing the number and intensity of shock tube generated blast waves leads to earlier retinal ganglion cell dysfunction and regional cell death

The purpose of this study was to examine the effect of a blast exposure generated from a shock tube on retinal ganglion cell (RGC) function and structure. Mice were exposed to one of three blast conditions using a shock tube; a single blast wave of 20 PSI, a single blast wave of 30 PSI, or three blast waves of 30 PSI given on three consecutive days with a one-day inter-blast interval. The structure and function of the retina were analyzed using the pattern electroretinogram (PERG), the optomotor reflex (OMR), and optical coherence tomography (OCT). The in vivo parameters were examined at baseline, and then again 1-week, 4-weeks, and 16-weeks following blast exposure. The number of surviving RGCs was quantified at the end of the study. Analysis of mice receiving a 20 PSI injury showed decreased PERG and OMR responses 16-weeks post blast, without evidence of changed retinal thickness or RGC death. Mice subjected to a 30 PSI injury showed decreased PERG responses 4 weeks and 16 weeks after injury, without changes in the retinal thickness or RGC density. Mice subjected to 30 PSI X 3 blast exposures had PERG deficits 1-week and 4-weeks post exposure. There was also significant change in retinal thickness 1-week and 16-weeks post blast exposure. Mice receiving 30 PSI X 3 blast injuries had regional loss of RGCs in the central retina, but not in the mid-peripheral or peripheral retina. Overall, this study has shown that increasing the number of blast exposures and the intensity leads to earlier functional loss of RGCs. We have also shown regional RGC loss only when using the highest blast intensity and number of blast injuries.

Mitochondrially Targeted Gene Therapy Rescues Visual Loss in a Mouse Model of Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON) is a common mitochondrial genetic disease, causing irreversible blindness in young individuals. Current treatments are inadequate, and there is no definitive cure. This study evaluates the effectiveness of delivering wildtype human NADH ubiquinone oxidoreductase subunit 4 (hND4) gene using mito-targeted AAV(MTSAAV) to rescue LHOH mice. We observed a declining pattern in electroretinograms amplitudes as mice aged across all groups (p < 0.001), with significant differences among groups (p = 0.023; Control vs. LHON, p = 0.008; Control vs. Rescue, p = 0.228). Inner retinal thickness and intraocular pressure did not change significantly with age or groups. Compared to LHON mice, those rescued with wildtype hND4 exhibited improved retinal visual acuity (0.29 ± 0.1 cy/deg vs. 0.15 ± 0.1 cy/deg) and increased functional hyperemia response (effect of flicker, p < 0.001, effect of Group, p = 0.004; Interaction Flicker × Group, p < 0.001). Postmortem analysis shows a marked reduction in retinal ganglion cell density in the LHON group compared to the other groups (Effect of Group, p < 0.001, Control vs. LHON, p < 0.001, Control vs. Rescue, p = 0.106). These results suggest that MTSAAV-delivered wildtype hND4 gene rescues, at least in part, visual impairment in an LHON mouse model and has the therapeutic potential to treat this disease.

Contributed Session III: The limits of resolution in the S-cone pathway.

The resolution of the S-cone pathway is first constrained by the density and arrangement of S-cones in the photoreceptor mosaic. Prior work comparing S-cone isolating visual acuity (sVA) to histological estimates of S-cone density has led to mixed conclusions, likely due to inter-individual differences in the S-cone sub-mosaic. We examined sVA in subjects with spectrally classified cone mosaics to test how the grain of the S-cone sub-mosaic limits resolution. Three observers whose cones were previously classified via adaptive optics (AO)-OCT based optoretinography participated in an sVA task at eccentricities ranging from 1.3° to 12.9° spread along all four cardinal meridians. Observers adapted to yellow light [CIE (0.45, 0.51); 200 cd/m2] for two minutes.Then, acuity was measured using a Tumbling 'E' task that showed blue [CIE (0.16, 0.044); 0.66 cd/m2) letters on the same yellow background, with an S-cone contrast of 0.93 (L/M-cone contrasts <0.01). Simultaneously recorded high-resolution AOSLO videos helped guide stimulus delivery to the spectrally classified retinal area. Measured sVAs were worse than predicted by the calculated S-cone Nyquist limit at all eccentricities, suggesting pooling of information from S-cones. Moreover, this pooling increased with eccentricity. While sVA does not follow the S-cone Nyquist limit, it is in good concordance with the Nyquist limit corresponding to known estimates of the sampling density of small bistratified retinal ganglion cells.

Evaluation of degeneration retinal ganglion cell loss in acute glaucoma model rats using syringe pump technique

Link of Video Abstract: https://youtu.be/vaGQXY-i4KE Introduction: Glaucoma is a neurodegenerative disorder marked by the gradual decline in function and degeneration of the retinal ganglion cells (RGCs) and their axons. The elevated intraocular pressure (IOP) is a predominant contributing factor to its onset. Employing laboratory animals to model glaucoma is a well-established strategy that serves the dual purpose of identifying disease mechanisms and developing novel neuroprotective approaches. The aim of this study was to develop a preclinical acute model of glaucoma based on controllable intraocular pressure with a syringe pump in rat Rattus norvegicus. Methods: This research was an animal-experimental study in animal model adult male Wistar rat (Rattus norvegicus), taken in May - October 2023 in an integrated laboratory Faculty of Veterinary Medicine Universitas Syiah Kuala. Total samples used in this research were 10 rats, divided into two categories which are control group (A) and treatment group (B) were given a pressure of 250 mmHg pressure in the right eye for 60 minutes. Apoptosis and degeneration of retinal ganglion cells after 8 weeks of elevated intraocular a pressure of 250 mmHg in the right eye for 60 minutes were observed by the HE staining. Result: A significant difference in IOP was noted between control group rat and treatment group rat. All rats that received treatment experienced an increase in IOP (100%). The RGC density decreased significantly in the treatment group rat (mean: 11.72 cell/field of view or lower 46.88%) compared with the control group (p =0.005). Conclusion: A pressure of 250 mmHg for 60 minutes has been proven to cause degeneration of the RGCs up to nearly 50% within a week. We tried a technique to induce increased IOP in rats as a model of acute glaucoma. Syringe pump technique can effectively induce acute ocular hypertension in rats, which causes progressive loss of retinal ganglion cells.

Cellular-Level Visualization of Retinal Pathology in Multiple Sclerosis With Adaptive Optics.

To apply adaptive optics-optical coherence tomography (AO-OCT) to quantify multiple sclerosis (MS)-induced changes in axonal bundles in the macular nerve fiber layer, ganglion cell somas, and macrophage-like cells at the vitreomacular interface. We used AO-OCT imaging in a pilot study of MS participants (n = 10), including those without and with a history of optic neuritis (ON, n = 4), and healthy volunteers (HV, n = 9) to reveal pathologic changes to inner retinal cells and structures affected by MS. We found that nerve fiber layer axonal bundles had 38% lower volume in MS participants (1.5 × 10-3 mm3) compared to HVs (2.4 × 10-3 mm3; P < 0.001). Retinal ganglion cell (RGC) density was 51% lower in MS participants (12.3 cells/mm2 × 1000) compared to HVs (25.0 cells/mm2 × 1000; P < 0.001). Spatial differences across the macula were observed in RGC density. RGC diameter was 15% higher in MS participants (11.7µm) compared to HVs (10.1µm; P < 0.001). A nonsignificant trend of higher density of macrophage-like cells in MS eyes was also observed. For all AO-OCT measures, outcomes were worse for MS participants with a history of ON compared to MS participants without a history of ON. AO-OCT measures were associated with key visual and physical disabilities in the MS cohort. Our findings demonstrate the utility of AO-OCT for highly sensitive and specific detection of neurodegenerative changes in MS. Moreover, the results shed light on the mechanisms that underpin specific neuronal pathology that occurs when MS attacks the retina. The new findings support the further development of AO-based biomarkers for MS.

Interspecies Retinal Diversity and Optic Nerve Anatomy in Odontocetes.

Throughout evolution, odontocete vision has had to readapt to the aquatic environment, which has had far-reaching effects on ocular anatomy and neurology. The most prominent features include the iris with an operculum, a well-developed choroid, the presence of giant ganglion cells in the retina, and the hemispherical shape of the thick eyecup. In the present study, the optic nerve and the retina were comparatively studied in Odontoceti (Cuvier's beaked whale, common bottlenose dolphin, false killer whale, long-finned pilot whale, Risso's dolphin, striped dolphin), the semi-aquatic common hippopotamus, and the fully terrestrial bovine. Cross-sections of the tissue were treated with histological and immunohistochemical techniques. Substantial differences were seen between the odontocetes and the reference species as well as within the cetaceans. The morphological structure of the optic nerve mainly appeared species specific, while the density of retinal ganglion cells was significantly higher in the terrestrial bovine than in the cetaceans. However, some typical characteristics of the cetacean retina were absent: the giant ganglion cells and the high retinal thickness. Immunohistochemical research showed varying degrees of neurofilament 200 expression in the retinal ganglion cells, while calretinin was only expressed in those of the common bottlenose dolphin and bovine.

Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.

Wolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS. Eight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis. DA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats. We present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.

Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma.

Much interest has been addressed to antioxidant dietary supplements that are known to lower the risk of developing glaucoma or delay its progression. Among them, niacin and citicoline protect retinal ganglion cells (RGCs) from degeneration by targeting mitochondria, though at different levels. A well-established mouse model of RGC degeneration induced by experimental intraocular pressure (IOP) elevation was used to investigate whether a novel combination of niacin/citicoline has better efficacy over each single component in preserving RGC health in response to IOP increase. Ocular hypertension was induced by an intracameral injection of methylcellulose that clogs the trabecular meshwork. Electroretinography and immunohistochemistry were used to evaluate RGC function and density. Oxidative, inflammatory and apoptotic markers were evaluated by Western blot analysis. The present results support an optimal efficacy of niacin with citicoline at their best dosage in preventing RGC loss. In fact, about 50% of RGCs were spared from death leading to improved electroretinographic responses to flash and pattern stimulation. Upregulated levels of oxidative stress and inflammatory markers were also consistently reduced by almost 50% after niacin with citicoline thus providing a significant strength to the validity of their combination. Niacin combined with citicoline is highly effective in restoring RGC physiology but its therapeutic potential needs to be further explored. In fact, the translation of the present compound to humans is limited by several factors including the mouse modeling, the higher doses of the supplements that are necessary to demonstrate their efficacy over a short follow up period and the scarce knowledge of their transport to the bloodstream and to the eventual target tissues in the eye.

Exendin-4 promotes retinal ganglion cell survival and function by inhibiting calcium channels in experimental diabetes

Progressive damage of retinal ganglion cells (RGCs) is observed in early diabetic retinopathy. Intracellular Ca2+ overload mediated by Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) is involved in neurodegeneration, whereas glucagon-like peptide-1 (GLP-1) provides neuroprotection. However, whether GLP-1 plays a neuroprotective role in diabetic retinas by modulating VGCCs remains unknown. We found that eye drops of exendin-4, a long-acting GLP-1 receptor (GLP-1R) agonist, prevented the increase of L-type Ca2+ current (ILCa) densities of RGCs induced by 4-week hyperglycemia and promoted RGC survival by suppressing L-type VGCC (L-VGCC) activity in streptozotocin-induced diabetic rats. Moreover, exendin-4-induced suppression of ILCa in RGCs may be mediated by a GLP-1R/Gs/cAMP-PKA/ryanodine/Ca2+/calmodulin/calcineurin/PP1 signaling pathway. Furthermore, exendin-4 functionally improved the light-evoked spiking ability of diabetic RGCs. These results suggest that GLP-1R activation enhances cAMP to PP1 signaling and that PP1 inactivates L-VGCCs by dephosphorylating them, thereby reducing Ca2+ influx, which could protect RGCs against excitotoxic Ca2+ overload.

Long-Term Effects on Retinal Structure and Function in a Mouse Endothelin-1 Model of Retinal Ganglion Cell Degeneration.

To study the long-term effects of endothelin-1 (ET-1)-induced retinal pathologies in mouse, using clinically relevant tools. Adult C57BL/6 mice (7-9 weeks old) were intravitreally injected with PBS (n = 10) or 0.25 (n = 8), 0.5 (n = 8), or 1 nmol ET-1 (n = 9) and examined using electroretinogram, optical coherence tomography (OCT), and Doppler OCT at baseline and postinjection days 10, 28, and 56. Retinal ganglion cell (RGC) survival in retinal whole mount was quantified at days 28 and 56. ET-1 induced immediate retinal arterial constriction. The significantly reduced total blood flow and positive scotopic threshold response in the 0.5- and 1-nmol ET-1 groups at day 10 were recovered at day 28. A-wave magnitude was also significantly reduced at days 10 and 28. While a comparable and significant reduction in retinal nerve fiber layer thickness was detected in all ET-1 groups at day 56, the 1-nmol group was the earliest to develop such change at day 28. All ET-1 groups showed a transient inner retinal layer thinning at days 10 and 28 and a plateaued outer layer thickness at days 10 to 56. The 1-nmol group showed a significant RGC loss over all retinal locations examined at day 28 as compared with PBS control. As for the lower-dosage groups, significant RGC density loss at central and midperipheral retina was detected at day 56 when compared with day 28. ET-1 injection in mice resulted in a transient vascular constriction and reduction in retinal functions, as well as a gradual loss of retinal nerve fiber layer and RGC in a dose-dependent manner.

Short-wavelength artificial light affects visual neural pathway development in mice

Nearly all modern life depends on artificial light; however, it does cause health problems. With certain restrictions of artificial light emitting technology, the influence of the light spectrum is inevitable. The most remarkable problem is its overload in the short wavelength component. Short wavelength artificial light has a wide range of influences from ocular development to mental problems. The visual neuronal pathway, as the primary light-sensing structure, may contain the fundamental mechanism of all light-induced abnormalities. However, how the artificial light spectrum shapes the visual neuronal pathway during development in mammals is poorly understood. We placed C57BL/6 mice in three different spectrum environments (full-spectrum white light: 400–750 nm; violet light: 400 ± 20 nm; green light: 510 ± 20 nm) beginning at eye opening, with a fixed light time of 7:00–19:00. During development, we assessed the ocular axial dimension, visual function and retinal neurons. After two weeks under short wavelength conditions, the ocular axial length (AL), anterior chamber depth (ACD) and length of lens thickness, real vitreous chamber depth and retinal thickness (LLVR) were shorter, visual acuity (VA) decreased, and retinal electrical activity was impaired. The density of S-cones in the dorsal and ventral retinas both decreased after one week under short wavelength conditions. In the ventral retina, it increased after three weeks. Retinal ganglion cell (RGC) density and axon thickness were not influenced; however, the axonal terminals in the lateral geniculate nucleus (LGN) were less clustered and sparse. Amacrine cells (ACs) were significantly more activated. Green light has few effects. The KEGG and GO enrichment analyses showed that many genes related to neural circuitry, synaptic formation and neurotransmitter function were differentially expressed in the short wavelength light group. In conclusion, exposure to short wavelength artificial light in the early stage of vision-dependent development in mice delayed the development of the visual pathway. The axon terminus structure and neurotransmitter function may be the major suffering.

Investigating the linkage between mesopic spatial summation and variations in retinal ganglion cell density across the central visual field.

The relationship between perimetric stimulus area and Ricco's area (RA) determines measured thresholds and the sensitivity of perimetry to retinal disease. The nature of this relationship, in addition to effect of retinal ganglion cell (RGC) number on this, is currently unknown for the adaptation conditions of mesopic microperimetry. In this study, achromatic mesopic spatial summation was measured across the central visual field to estimate RA with the number of RGCs underlying RA also being established. Achromatic luminance thresholds were measured for six incremental spot stimuli (0.009-2.07 deg2 ) and 190.4 ms duration, at four locations, each at 2.5°, 5° and 10° eccentricity in five healthy observers (mean age 61.4 years) under mesopic conditions (background 1.58 cd/m2 ). RA was estimated using two-phase regression analysis with the number of RGCs underlying RA being calculated using normative histological RGC counts. Ricco's area exhibited a small but statistically insignificant increase between 2.5° and 10° eccentricity. Compared with photopic conditions, RA was larger, with the difference between RA and the Goldmann III stimulus (0.43°) being minimised. RGC number underlying RA was also higher than reported for photopic conditions (median 70 cells, IQR 36-93), with no significant difference being observed across test locations. Ricco's area and the number of RGCs underlying RA do not vary significantly across the central visual field in mesopic conditions. However, RA is larger and more similar to the standard perimetric Goldmann III stimulus under mesopic compared with photopic adaptation conditions. Further work is required to determine if compensatory enlargements in RA occur in age-related macular degeneration, to establish the optimal stimulus parameters for AMD-specific microperimetry.