Molecular Mechanisms of Retinal Degeneration and How to Avoid It.

Vision is the most important sensory modality in vertebrates in general, and as such, it is the most feared sense to lose [...].

Traumatic Brain Injury Induces Microglial and Caspase3 Activation in the Retina.

Traumatic brain injury (TBI) is among the main causes of sudden death after head trauma. These injuries can result in severe degeneration and neuronal cell death in the CNS, including the retina, which is a crucial part of the brain responsible for perceiving and transmitting visual information. The long-term effects of mild-repetitive TBI (rmTBI) are far less studied thus far, even though damage induced by repetitive injuries occurring in the brain is more common, especially amongst athletes. rmTBI can also have a detrimental effect on the retina and the pathophysiology of these injuries is likely to differ from severe TBI (sTBI) retinal injury. Here, we show how rmTBI and sTBI can differentially affect the retina. Our results indicate an increase in the number of activated microglial cells and Caspase3-positive cells in the retina in both traumatic models, suggesting a rise in the level of inflammation and cell death after TBI. The pattern of microglial activation appears distributed and widespread but differs amongst the various retinal layers. sTBI induced microglial activation in both the superficial and deep retinal layers. In contrast to sTBI, no significant change occurred following the repetitive mild injury in the superficial layer, only the deep layer (spanning from the inner nuclear layer to the outer plexiform layer) shows microglial activation. This difference suggests that alternate response mechanisms play a role in the case of the different TBI incidents. The Caspase3 activation pattern showed a uniform increase in both the superficial and deep layers of the retina. This suggests a different action in the course of the disease in sTBI and rmTBI models and points to the need for new diagnostic procedures. Our present results suggest that the retina might serve as such a model of head injuries since the retinal tissue reacts to both forms of TBI and is the most accessible part of the human brain.

Unmasking inhibition prolongs neuronal function in retinal degeneration mouse model.

All neurodegenerative diseases involve a relatively long period of timeframe from the onset of the disease to complete loss of functions. Extending this timeframe, even at a reduced level of function, would improve the quality of life of patients with these devastating diseases. The retina, as the part of the central nervous system and a frequent site of many distressing neurodegenerative disease, provides an ideal model to investigate the feasibility of extending the functional timeframe through pharmacologic intervention. Retinitis Pigmentosa (RP) is a group of blinding diseases. Although the rate of progression and degree of visual loss varies, there is usually a prolonged time before patients totally lose their photoreceptors and vision. It is believed that inhibitory mechanisms are still intact and may become relatively strong after the gradual loss of photoreceptors in RP patients. Therefore, it is possible that light-evoked responses of retinal ganglion cells and visual information processes in retinal circuits could be "unmasked" by blocking these inhibitory mechanisms restoring some level of visual function. Our results indicate that if the inhibition in the inner retina was unmasked in the retina of the rd10 mouse (the well-characterized RP mimicking, clinically relevant mouse model), the light-evoked responses of many retinal ganglion cells can be induced and restore their normal light sensitivity. GABA A receptor plays a major role in this masking inhibition. ERG b-wave and behavioral tests of spatial vision partly recovered after the application of PTX. Hence, removing retinal inhibition unmasks signalling mediated by surviving cones, thereby restoring some degree of visual function. These results may offer a novel strategy to restore the visual function with the surviving cones in RP patients and other gradual and progressive neurodegenerative diseases.

LED-Induced Microglial Activation and Rise in Caspase3 Suggest a Reorganization in the Retina.

Vision is our primary sense as the human eye is the gateway for more than 65% of information reaching the human brain. Today's increased exposure to different wavelengths and intensities of light from light emitting diode (LED) sources could induce retinal degeneration and accompanying neuronal cell death. Damage induced by chronic phototoxic reactions occurring in the retina accumulates over years and it has been suggested as being responsible for the etiology of many debilitating ocular conditions. In this work, we examined how LED stimulation affects vision by monitoring changes in the expression of death and survival factors as well as microglial activation in LED-induced damage (LID) of the retinal tissue. We found an LED-exposure-induced increase in the mRNA levels of major apoptosis-related markers BAX, Bcl-2, and Caspase-3 and accompanying widespread microglial and Caspase-3 activation. Everyday LED light exposure was accounted for in all the described changes in the retinal tissue of mice in this study, indicating that overuse of non-filtered direct LED light can have detrimental effects on the human retina as well.

Imatinib Sets Pericyte Mosaic in the Retina.

The nervous system demands an adequate oxygen and metabolite exchange, making pericytes (PCs), the only vasoactive cells on the capillaries, essential to neural function. Loss of PCs is a hallmark of multiple diseases, including diabetes, Alzheimer's, amyotrophic lateral sclerosis (ALS) and Parkinson's. Platelet-derived growth factor receptors (PDGFRs) have been shown to be critical to PC function and survival. However, how PDGFR-mediated PC activity affects vascular homeostasis is not fully understood. Here, we tested the hypothesis that imatinib, a chemotherapeutic agent and a potent PDGFR inhibitor, alters PC distribution and thus induces vascular atrophy. We performed a morphometric analysis of the vascular elements in sham control and imatinib-treated NG2-DsRed mice. Vascular morphology and the integrity of the blood-retina barrier (BRB) were evaluated using blood albumin labeling. We found that imatinib decreased the number of PCs and blood vessel (BV) coverage in all retinal vascular layers; this was accompanied by a shrinkage of BV diameters. Surprisingly, the total length of capillaries was not altered, suggesting a preferential effect of imatinib on PCs. Furthermore, blood-retina barrier disruption was not evident. In conclusion, our data suggest that imatinib could help in treating neurovascular diseases and serve as a model for PC loss, without BRB disruption.

Expression of Ca2+-Binding Buffer Proteins in the Human and Mouse Retinal Neurons.

Ca2+-binding buffer proteins (CaBPs) are widely expressed by various neurons throughout the central nervous system (CNS), including the retina. While the expression of CaBPs by photoreceptors, retinal interneurons and the output ganglion cells in the mammalian retina has been extensively studied, a general description is still missing due to the differences between species, developmental expression patterns and study-to-study discrepancies. Furthermore, CaBPs are occasionally located in a compartment-specific manner and two or more CaBPs can be expressed by the same neuron, thereby sharing the labor of Ca2+ buffering in the intracellular milieu. This article reviews this topic by providing a framework on CaBP functional expression by neurons of the mammalian retina with an emphasis on human and mouse retinas and the three most abundant and extensively studied buffer proteins: parvalbumin, calretinin and calbindin.

Inhibitory masking controls the threshold sensitivity of retinal ganglion cells.

KEY POINTS: Retinal ganglion cells (RGCs) in dark-adapted retinas show a range of threshold sensitivities spanning ∼3 log units of illuminance. Here, we show that the different threshold sensitivities of RGCs reflect an inhibitory mechanism that masks inputs from certain rod pathways. The masking inhibition is subserved by GABAC receptors, probably on bipolar cell axon terminals. The GABAergic masking inhibition appears independent of dopaminergic circuitry that has been shown also to affect RGC sensitivity. The results indicate a novel mechanism whereby inhibition controls the sensitivity of different cohorts of RGCs. This can limit and thereby ensure that appropriate signals are carried centrally in scotopic conditions when sensitivity rather than acuity is crucial. ABSTRACT: The responses of rod photoreceptors, which subserve dim light vision, are carried through the retina by three independent pathways. These pathways carry signals with largely different sensitivities. Retinal ganglion cells (RGCs), the output neurons of the retina, show a wide range of sensitivities in the same dark-adapted conditions, suggesting a divergence of the rod pathways. However, this organization is not supported by the known synaptic morphology of the retina. Here, we tested an alternative idea that the rod pathways converge onto single RGCs, but inhibitory circuits selectively mask signals so that one pathway predominates. Indeed, we found that application of GABA receptor blockers increased the sensitivity of most RGCs by unmasking rod signals, which were suppressed. Our results indicate that inhibition controls the threshold responses of RGCs under dim ambient light. This mechanism can ensure that appropriate signals cross the bottleneck of the optic nerve in changing stimulus conditions.

Calcium buffer proteins are specific markers of human retinal neurons.

Ca(2+)-buffer proteins (CaBPs) modulate the temporal and spatial characteristics of transient intracellular Ca(2+)-concentration changes in neurons in order to fine-tune the strength and duration of the output signal. CaBPs have been used as neurochemical markers to identify and trace neurons of several brain loci including the mammalian retina. The CaBP content of retinal neurons, however, varies between species and, thus, the results inferred from animal models cannot be utilised directly by clinical ophthalmologists. Moreover, the shortage of well-preserved human samples greatly impedes human retina studies at the cellular and network level. Our purpose has therefore been to examine the distribution of major CaBPs, including calretinin, calbindin-D28, parvalbumin and the recently discovered secretagogin in exceptionally well-preserved human retinal samples. Based on a combination of immunohistochemistry, Neurolucida tracing and Lucifer yellow injections, we have established a database in which the CaBP marker composition can be defined for morphologically identified cell types of the human retina. Hence, we describe the full CaBP make-up for a number of human retinal neurons, including HII horizontal cells, AII amacrine cells, type-1 tyrosine-hydroxylase-expressing amacrine cells and other lesser known neurons. We have also found a number of unidentified cells whose morphology remains to be characterised. We present several examples of the colocalisation of two or three CaBPs with slightly different subcellular distributions in the same cell strongly suggesting a compartment-specific division of labour of Ca(2+)-buffering by CaBPs. Our work thus provides a neurochemical framework for future ophthalmological studies and renders new information concerning the cellular and subcellular distribution of CaBPs for experimental neuroscience.

The Retinal TNAP.

Accumulating evidence from recent literature underline the important roles of tissue non specific alkaline phosphatase (TNAP) in diverse functions as well as diseases of the nervous system. Exploration of TNAP in well characterized neural circuits such as the retina, might significantly advance our understanding regarding neural TNAP's roles. This chapter reviews the scarce literature as well as our findings on retinal TNAP. We found that retinal TNAP activity was preserved and followed diverse patterns throughout vertebrate evolution. We have consistently observed TNAP activity (1) in retinal vessels, (2) in photoreceptors and (3) in the majority of the studied species in the outer (OPL) and inner plexiform layers (IPL), where synaptic transmission occurs. Importantly, in some species the IPL exhibits several TNAP positive strata. These strata exactly corresponded those seen after quadruple immunohistochemistry with four canonical IPL markers (tyrosine hydroxylase, choline acetyltransferase, calretinin, protein kinase C α). Diabetes results in diminishing retinal TNAP activity before changes in canonical markers could be observed in a rat model. The presence of TNAP activity at critical sites of neurotransmission suggests its important and evolutionary conserved role in vision. In diabetes, the decreased TNAP activity indicates neurological alterations adding further evidence for the role of TNAP in brain diseases.

Gap junction-mediated death of retinal neurons is connexin and insult specific: a potential target for neuroprotection.

Secondary cell death via gap junctions (GJs) plays a role in the propagation of neuronal loss under a number of degenerative disorders. Here, we examined the role of GJs in neuronal death in the retina, which has arguably the most diverse expression of GJs in the CNS. Initially, we induced apoptotic death by injecting single retinal ganglion cells and glia with cytochrome C and found that this resulted in the loss of neighboring cells to which they were coupled via GJs. We next found that pharmacological blockade of GJs eradicated nearly all amacrine cell loss and reduced retinal ganglion cell loss by ∼70% after induction of either excitotoxic or ischemic insult conditions. These data indicate that the GJ-mediated secondary cell death was responsible for the death of most cells. Whereas genetic deletion of the GJ subunit Cx36 increased cell survivability by ∼50% under excitotoxic condition, cell loss in Cx45 knock-out mouse retinas was similar to that seen in wild-type mice. In contrast, ablation of Cx45 reduced neuronal loss by ∼50% under ischemic insult, but ablation of Cx36 offered no protection. Immunolabeling of the connexins showed differential changes in protein expression consistent with their differing roles in propagating death signals under the two insults. These data indicate that secondary cell death is mediated by different cohorts of GJs dependent on the connexins they express and the type of initial insult. Our results suggest that targeting specific connexins offers a novel therapeutic strategy to reduce progressive cell loss under different neurodegenerative conditions.

Tyrosine hydroxylase positive perisomatic rings are formed around various amacrine cell types in the mammalian retina.

Dopaminergic neurons of the central nervous system are mainly found in nuclei of the midbrain and the hypothalamus that provide subcortical and cortical targets with a rich and divergent innervation. Disturbance of signaling through this system underlies a variety of deteriorating conditions such as Parkinson's disease and schizophrenia. Although retinal dopaminergic signaling is largely independent of the above circuitry, malfunction of the retinal dopaminergic system has been associated with anomalies in visual adaptation and a number of retinal disorders. Dopamine (DA) is released mainly in a paracrine manner by a population of tyrosine hydroxylase expressing (TH(+) ) amacrine cells (AC) of the mammalian retina; thus DA reaches virtually all retinal cell types by diffusion. Despite this paracrine release, however, the so called AII ACs have been considered as the main targets of DA signaling owing to a characteristic and robust ring-like TH(+) innervation to the soma/dendritic-stalk area of AII cells. This apparent selectivity of TH(+) innervation seems to contradict the divergent DAergic signaling scheme of other brain loci. In this study, however, we show evidence for intimate proximity between TH(+) rings and somata of neurochemically identified non-AII cells. We also show that this phenomenon is not species specific, as we observe it in popular mammalian animal models including the rabbit, the rat, and the mouse. Finally, our dataset suggests the existence of further, yet unidentified post-synaptic targets of TH(+) dendritic rings. Therefore, we hypothesize that TH(+) ring-like structures target the majority of ACs non-selectively and that such contacts are wide-spread among mammals. Therefore, this new view of inner retinal TH(+) innervation resembles the divergent DAergic innervation of other brain areas through the mesolimbic, mesocortical, and mesostriatal signaling streams. AII amacrine cells have been considered as the main targets of dopamine signaling in the mammalian retina owing to a characteristic ring-like innervation from dopaminergic (TH(+) ) amacrine cells (green) to somata of AII cells (red). In this study, we show the intimate proximity of TH(+) rings and somata of non-AII cells, including starburst-a amacrine cells (blue) and other unidentified amacrine cells (magenta). We find that this phenomenon is not species specific and it occurs in a number of popular mammalian animal models. We hypothesize that TH(+) ring-inputs target most amacrine cells non-selectively and thus it resembles the divergent dopaminergic innervation of other brain areas.

Stratified organization and disorganization of inner plexiform layer revealed by TNAP activity in healthy and diabetic rat retina.

Tissue non-specific alkaline phosphatase (TNAP), an abundant ectophosphatase, is present in various organs including the brain and retina of several vertebrate species. Evidence is emerging that TNAP influences neural functions in multiple ways. In rat, strong TNAP activity has been found in retinal vessels, photoreceptors, and both synaptic layers. In the present study, we identified eleven strata of the inner plexiform layer (IPL) by using TNAP histochemistry alone. The TNAP strata corresponded exactly to the strata seen after combined immunohistochemistry with four canonical IPL markers (TH-ChAT-CR-PKCα). Therefore, as described in other mammalian species, our data support the existence of multiple morphologically and functionally discernible IPL strata in rats. Remarkably, the stratification pattern of the IPL was severely disrupted in a diabetic rat model, even before changes in the canonical IPL markers were detectable. These findings indicate that TNAP histochemistry offers a more straightforward, but also more sensitive, method for investigating retinal strata and their diabetes-induced degeneration.

Developmental changes in the expression level of connexin36 in the rat retina.

Connexin36 (Cx36) is the major gap junction forming protein in the brain and the retina; thus, alterations in its expression indicate changes in the corresponding circuitry. Many structural changes occur in the early postnatal retina before functional neuronal circuits are finalized, including those that incorporate gap junctions. To reveal the time-lapse formation of inner retinal gap junctions, we examine the developing postnatal rat retina from birth (P0) to young adult age (P20) and follow the expression of Cx36 in the mRNA and protein levels. We found a continuous elevation in the expression of both the Cx36 transcript and protein between P0 and P20 and a somewhat delayed Cx36 plaque formation throughout the inner plexiform layer (IPL) starting at P10. By using tristratificated calretinin positive (CaR(+)) fibers in the IPL as a guide, we detected a clear preference of Cx36 plaques for the ON sublamina from the earliest time of detection. This distributional preference became more pronounced at P15 and P20 due to the emergence and widespread expression of large (>0.1 µm(2)) Cx36 plaques in the ON sublamina. Finally, we showed that parvalbumin-positive (PV(+)) AII amacrine cell dendrites colocalize with Cx36 plaques as early as P10 in strata 3 and 4, whereas colocalizations in stratum 5 became characteristic only around P20. We conclude that Cx36 expression in the rat IPL displays a characteristic succession of changes during retinogenesis reflecting the formation of the underlying electrical synaptic circuitry. In particular, AII cell gap junctions, first formed with ON cone bipolar cells and later with other AII amacrine cells, accounted for the observed Cx36 expressional changes.

TNAP activity is localized at critical sites of retinal neurotransmission across various vertebrate species.

Evidence is emerging with regard to the role of tissue non-specific alkaline phosphatase (TNAP) in neural functions. As an ectophosphatase, this enzyme might influence neural activity and synaptic transmission in diverse ways. The localization of the enzyme in known neural circuits, such as the retina, might significantly advance an understanding of its role in normal and pathological functioning. However, the presence of TNAP in the retina is scarcely investigated. Our multispecies comparative study (zebrafish, cichlid, frog, chicken, mouse, rat, golden hamster, guinea pig, rabbit, sheep, cat, dog, ferret, squirrel monkey, human) using enzyme histochemistry and Western blots has shown the presence of TNAP activity in the retina of several mammalian species, including humans. Although the TNAP activity pattern varies across species, we have observed the following trends: (1) in all investigated species (except golden hamster), retinal vessels display TNAP activity; (2) TNAP activity consistently occurs in the photoreceptor layer; (3) in majority of the investigated species, marked TNAP activity is present in the outer and inner plexiform layers. In zebrafish, frog, chicken, guinea pig, and rat, TNAP histochemistry has revealed several sublayers of the inner plexiform layer. Frog, golden hamster, guinea pig, mouse, and human retinas possess a subpopulation of amacrine cells positively staining for TNAP activity. The expression of TNAP in critical sites of retinal signal transmission across a wide range of species suggests its fundamental, evolutionally conserved role in vision.

The diverse functional roles and regulation of neuronal gap junctions in the retina.

Electrical synaptic transmission through gap junctions underlies direct and rapid neuronal communication in the CNS. The diversity of functional roles that electrical synapses have is perhaps best exemplified in the vertebrate retina, in which gap junctions are formed by each of the five major neuron types. These junctions are dynamically regulated by ambient illumination and by circadian rhythms acting through light-activated neuromodulators such as dopamine and nitric oxide, which in turn activate intracellular signalling pathways in the retina.The networks formed by electrically coupled neurons are plastic and reconfigurable, and those in the retina are positioned to play key and diverse parts in the transmission and processing of visual information at every retinal level.

Gap junctions fine-tune ganglion cell signals to equalize response kinetics within a given electrically coupled array.

Retinal ganglion cells (RGCs) summate inputs and forward a spike train code to the brain in the form of either maintained spiking (sustained) or a quickly decaying brief spike burst (transient). We report diverse response transience values across the RGC population and, contrary to the conventional transient/sustained scheme, responses with intermediary characteristics are the most abundant. Pharmacological tests showed that besides GABAergic inhibition, gap junction (GJ)-mediated excitation also plays a pivotal role in shaping response transience and thus visual coding. More precisely GJs connecting RGCs to nearby amacrine and RGCs play a defining role in the process. These GJs equalize kinetic features, including the response transience of transient OFF alpha (tOFFα) RGCs across a coupled array. We propose that GJs in other coupled neuron ensembles in the brain are also critical in the harmonization of response kinetics to enhance the population code and suit a corresponding task.

Serotonin is a gap junction-permeable neuronal tracer in the mouse retina.

Introduction: Gap junctions are dynamically modulated bridges allowing the transcellular passage of ions and small molecules with a molecular mass of up to 1 kDa, a mechanism utilized for molecular communication purposes by living cells. This same mechanism is also exploited by scientists to reveal the existence of gap junction contacts by the cell-to-cell movement of tracers. However, multiple labeling experiments require the availability of multiple gap junction-permeable tracers. Methods: To this end, we utilized the well-known transient OFF alpha retinal ganglion cell (RGC)-coupled array as a model system to study and compare the transjunctional movement of neurobiotin (NB), a commonly used tracer, and serotonin, a recently identified tracer. Results: Although the transjunctional movement of serotonin has been established in cell cultures, here we show, for the first time, that serotonin is also a potent tracer in in vitro tissue. In addition, serotonin is lighter than the classical gap junction-permeable NB, and thus, we expected that tracer movement would be comparable to or better than that of serotonin. We found that intracellular serotonin injections result in the labeling of the coupled transient OFF alpha RGC array very similar to those of the classical NB-labeled arrays. Both serotonin and NB-injected transient OFF alpha RGCs displayed the well-known pattern with coupled RGCs and a cohort of coupled wide-field amacrine cells (ACs). Discussion: By using morphological characteristics, we confirm that the serotonin and the NB-coupled AC arrays are identical, and thereby confirm that serotonin is a potent gap junction-permeable tracer and can be readily used as an alternative to NB in in vitro tissue. Moreover, serotonin can be utilized in parallel with other dyes or tracers, enabling the use of multiple labels in the same material.

Extrinsic and Intrinsic Factors Determine Expression Levels of Gap Junction-Forming Connexins in the Mammalian Retina.

Gap junctions (GJs) are not static bridges; instead, GJs as well as the molecular building block connexin (Cx) proteins undergo major expression changes in the degenerating retinal tissue. Various progressive diseases, including retinitis pigmentosa, glaucoma, age-related retinal degeneration, etc., affect neurons of the retina and thus their neuronal connections endure irreversible changes as well. Although Cx expression changes might be the hallmarks of tissue deterioration, GJs are not static bridges and as such they undergo adaptive changes even in healthy tissue to respond to the ever-changing environment. It is, therefore, imperative to determine these latter adaptive changes in GJ functionality as well as in their morphology and Cx makeup to identify and distinguish them from alterations following tissue deterioration. In this review, we summarize GJ alterations that take place in healthy retinal tissue and occur on three different time scales: throughout the entire lifespan, during daily changes and as a result of quick changes of light adaptation.

Transience of the Retinal Output Is Determined by a Great Variety of Circuit Elements.

Retinal ganglion cells (RGCs) encrypt stimulus features of the visual scene in action potentials and convey them toward higher visual centers in the brain. Although there are many visual features to encode, our recent understanding is that the ~46 different functional subtypes of RGCs in the retina share this task. In this scheme, each RGC subtype establishes a separate, parallel signaling route for a specific visual feature (e.g., contrast, the direction of motion, luminosity), through which information is conveyed. The efficiency of encoding depends on several factors, including signal strength, adaptational levels, and the actual efficacy of the underlying retinal microcircuits. Upon collecting inputs across their respective receptive field, RGCs perform further analysis (e.g., summation, subtraction, weighting) before they generate the final output spike train, which itself is characterized by multiple different features, such as the number of spikes, the inter-spike intervals, response delay, and the rundown time (transience) of the response. These specific kinetic features are essential for target postsynaptic neurons in the brain in order to effectively decode and interpret signals, thereby forming visual perception. We review recent knowledge regarding circuit elements of the mammalian retina that participate in shaping RGC response transience for optimal visual signaling.

Masked excitatory crosstalk between the ON and OFF visual pathways in the mammalian retina.

A fundamental organizing feature of the visual system is the segregation of ON and OFF responses into parallel streams to signal light increment and decrement. However, we found that blockade of GABAergic inhibition unmasks robust ON responses in OFF α-ganglion cells (α-GCs). These ON responses had the same centre-mediated structure as the classic OFF responses of OFF α-GCs, but were abolished following disruption of the ON pathway with L-AP4. Experiments showed that both GABA(A) and GABA(C) receptors are involved in the masking inhibition of this ON response, located at presynaptic inhibitory synapses on bipolar cell axon terminals and possibly amacrine cell dendrites. Since the dendrites of OFF α-GCs are not positioned to receive excitatory inputs from ON bipolar cell axon terminals in sublamina-b of the inner plexiform layer (IPL), we investigated the possibility that gap junction-mediated electrical synapses made with neighbouring amacrine cells form the avenue for reception of ON signals. We found that the application of gap junction blockers eliminated the unmasked ON responses in OFF α-GCs, while the classic OFF responses remained. Furthermore, we found that amacrine cells coupled to OFF α-GCs display processes in both sublaminae of the IPL, thus forming a plausible substrate for the reception and delivery of ON signals to OFF α-GCs. Finally, using a multielectrode array, we found that masked ON and OFF signals are displayed by over one-third of ganglion cells in the rabbit and mouse retinas, suggesting that masked crossover excitation is a widespread phenomenon in the inner mammalian retina.