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PubMed1977

Structural basis for on-and off-center responses in retinal bipolar cells.

Electron microscopy of Golgi preparations of goldfish retina shows that dendrites of type a (hyperpolarizing, off-center) bipolar cells make wide cleft junctions unassociated with synaptic ribbons, while those of type b (depolarizing, on-center) bioplar cells make narrow cleft junctions and synaptic ribbon contacts, with rods and cones. This suggests that wide cleft junctions are the site of sign-conserving, and narrow cleft junctions or ribbon contacts (or both) are the site of sign-inverting synaptic transmission from photoreceptors to bipolars.

Animals↗
PubMed1976

Blindness caused by photoreceptor degeneration as a remote effect of cancer.

Three postmenopausal women developed photoreceptor degeneration one to four months preceding or following discovery of an anaplastic tumor. Two patients had transitory visual obscurations and bizarre visual sensations. Ring scotomas progressed to severe visual field loss. Retinal arteries were markedly narrowed. Electroretinograms revealed almost total absence of response in one patient, and another complained of the recent onset of night blindness. In all three patients severe degeneration of the photoreceptor cells associated with melanophagic activity was shown histologically. In two patients neuropathologic examination from the retinal bipolar cells to the occipital cortex revealed no significant alterations.

Aged↗
PubMed2026

Long-term functional synaptic integration of genome-edited retinal organoids in a primate model of macular degeneration.

Retinal organoids represent a promising regenerative strategy for restoring vision in retinal degenerative diseases, but the capacity of host cone bipolar cells in the primate macula to rewire with transplanted photoreceptors has not been established. In this study, we transplanted genome-edited ISL1-/- human retinal organoids lacking ON-bipolar cells into an acute laser-induced macular photoreceptor ablation non-human primate model. Using immunohistochemistry, ultrastructural imaging, and focal macular electroretinography, we demonstrate that host rod and cone bipolar cells actively extend dendrites toward grafted photoreceptors and form synaptic contacts, with evidence of functional signal transmission in a subset of transplanted eyes. Longitudinal, per-eye analyses revealed that host ON-bipolar responses improved in two of four eyes with ISL1-/- graft by up to 21.6% and remained stable for up to 2 years post transplantation. Moreover, OFF-pathway connectivity showed potential progressive maturation, with delayed increase in d-wave after 13 months in one of those eyes. These findings provide the first demonstration of long-term anatomical host-graft synaptic integration in the primate macula, establishing that central cone bipolar circuits retain the capacity for durable rewiring with human stem-cell-derived grafts. Our results highlight ISL1-/- retinal organoids as a promising approach for central vision restoration in macular degeneration.

Animals↗
PubMed1979

Demonstration of a somatostatin-like activity in retinal cells of the rat.

A somatostatin-like substance is demonstrated by light microscopic immunohistochemistry (PAP-method) in perikarya and cell processes of the retina of adult and infant rats. These perikarya are identified according to their size, arrangement and distribution. Each of the first two neuronal orders (receptors, bipolar cells, ganglionic cells) of the visual pathway can be associated with retinal cells reacting positively with anti-somatostatin. In the adult rat, perikarya and processes of (i) horizontal cells, (ii) amacrine cells and (iii) large neurons in the ganglionic layer are specifically labeled. The staining of middle-sized and small ganglion cells is probably caused by the close attachment of labeled fibers to non-reacting cells. Postnatally, the immunoreactive elements develop in parallel to the differentiation of the corresponding retinal layers. It is discussed whether the three types of retinal cells containing a somatostatin-like substance provide an inhibitory system to each of the two orders of retinal neurons.

Age Factors↗
PubMed2026

Generation of a New Immunodeficient Rat Model of Retinal Degeneration With LSL TdTomato Reporter and TdTomato-Pcp2 Expression.

PURPOSE: The purpose of this study was to develop a fluorescently labeled immunodeficient retinal degenerate (RD) rat model for studying photoreceptor degeneration and transplant-host connectivity using the Cre-lox system. METHODS: We developed gene constructs for CAG-LSL-TdTomato (expressing floxed TdTomato) and Pcp2-Cre (marker for ON-bipolar cells) that were injected into rat embryos. The LSL TdTomato reporter strain, created on immunodeficient RhoS334ter-3 rats (RRRC #539), was bred to homozygosity (strain SD-Foxn1rnuTg((Rho-S334X)3,CAG-TdTomato)1010Mjsuc, RRRC #1055, "RNT"). The gene construct Pcp2-Cre was injected into Long-Evans (LE) rat embryos, resulting in two Pcp2-cre founders (strain PCP2 Cre-1105 RKI, "Pcp2"), with targeted and targeted/random insertion of the transgene. F1 offspring were bred to homozygosity and immunodeficiency. To test whether TdTomato expression can be induced in "RNT" rats expressing floxed TdTomato, retinal explants of P9 "RNT" rats were exposed to AAV-PHP.eB-hSyn-myc-Cre (AAV-Syn-Cre) virus. Homozygous rats of both strains ("RNT" and Pcp2-Cre) were crossbred to generate RD TdTomato-Pcp2 ("RTP") rats. Retinas were stained for various retinal markers. GFP-expressing rat retinas were transplanted to 6-week-old "RTP" rats and analyzed after 37 and 77 days. RESULTS: AAV-Syn-Cre induced TdTomato expression in "RNT" retinas. TdTomato-Pcp2 RD rats developed RD similar to the original Rho S334ter-3 rats. Retinas with targeted Pcp2-Cre insertion showed TdTomato in retinal interneurons, overlapping with Pcp2-staining ON bipolar cells, and cones. Retinas with random Pcp2-Cre insertion exhibited additional TdTomato in many other cells. Pcp2-TdTomato expression defined transplant-host boundaries. CONCLUSIONS: We created a unique RD rat model for studying retinal transplant connectivity which can also be used to generate RD rats with other cell-specific labels. TRANSLATIONAL RELEVANCE: This newly created rat is useful for cell therapy and retinal degeneration studies.

Animals↗
PubMed1977

Subsurface cisterns in the Cynomolgus retina.

Subsurface cisterns were found in retinal neurons of the Cynomolgus monkey. They were located in amacrine, bipolar and ganglion cells and were associated with the rough endoplasmic reticulum. Subsurface cisterns were not found in Müller cells. The possible functional significance of the subsurface cisterns is discussed.

Animals↗
PubMed2023

Retinal Phenotyping of a Murine Model of Lafora Disease.

Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a-/- mice by examining knockout (KO; Epm2a-/-) and control (WT) littermates at two time points (10 and 14 months, respectively). In vivo exams included electroretinogram (ERG) testing, optical coherence tomography (OCT) and retinal photography. Ex vivo retinal testing included Periodic acid Schiff Diastase (PASD) staining, followed by imaging to assess and quantify LB deposition. There was no significant difference in any dark-adapted or light-adapted ERG parameters between KO and WT mice. The total retinal thickness was comparable between the groups and the retinal appearance was normal in both groups. On PASD staining, LBs were observed in KO mice within the inner and outer plexiform layers and in the inner nuclear layer. The average number of LBs within the inner plexiform layer in KO mice were 1743 ± 533 and 2615 ± 915 per mm2, at 10 and 14 months, respectively. This is the first study to characterize the retinal phenotype in an Epm2a-/- mouse model, demonstrating significant LB deposition in the bipolar cell nuclear layer and its synapses. This finding may be used to monitor the efficacy of experimental treatments in mouse models.

Mice↗
PubMed2026

Transient YAP activation uncovers the neurogenic potential of proliferative mammalian Müller glia.

The Hippo pathway effector YAP promotes spontaneous proliferation of Müller glia (MG), suggesting that bypassing Hippo signaling and activating YAP could enhance retinal regeneration. However, whether proliferative adult MGs retain meaningful neurogenic competence remains unclear. Here, using viral delivery of a Hippo-resistant YAP variant to wild-type adult MGs, we achieved transient YAP activation in adult MGs, inducing proliferation followed by cell-cycle withdrawal and differentiation. Intersectional genetic lineage tracing and EdU labeling, combined with transcriptomic analyses, revealed that YAP-activated MGs predominantly regenerate MGs, whereas only a subset gives rise to bipolar cell-like neurons. These results indicate that proliferative MGs acquire a state resembling that of late-stage retinal progenitors, with limited neurogenic lineage potential. We conclude that YAP-activated cell-cycle reentry inefficiently reprograms adult MGs toward photoreceptor or ganglion cell fates. These findings define the limited competence of proliferative adult MGs to contribute to neurogenic fates and provide a rigorous framework for assessing in vivo glial reprogramming strategies.

AAV↗
PubMed2026

EGFLAM Pathogenic Variants and Congenital Stationary Night Blindness.

IMPORTANCE: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous inherited retinal disorder (IRD), and in many complete CSNB (cCSNB) cases, the underlying genetic cause remains unknown. Uncovering the genetic defects of IRDs helps to refine diagnostic methods and supports the development of specific therapeutic approaches. OBJECTIVE: To describe the phenotype and the underlying gene defect in patients with cCSNB from 2 unrelated families. DESIGN, SETTING AND PARTICIPANTS: This retrospective case series was conducted from January 2023 to July 2025. Data for 3 patients from cohorts of genetically unsolved IRD cases in France (n = 140 for CSNB) and the Netherlands (n = 2730 for IRD) were analyzed clinically and genetically. EXPOSURES: Complete ocular examination, including multimodal retinal imaging and full-field electroretinography (ffERG) incorporating the International Society for Clinical Electrophysiology of Vision standards and multimodal retinal imaging, were performed. Gene defects were identified by genome sequencing (GS) and exome sequencing (ES). MAIN OUTCOMES AND MEASURES: The main outcome was a gene defect, EGFLAM, underlying cCSNB. Measures included phenotyping, GS, ES, Sanger sequencing, and cosegregation analysis. RESULTS: The series included 3 patients from 2 unrelated families of Moroccan ancestry showing high myopia, reduced visual acuity, and night blindness. Retinal imaging depicted myopic changes. ffERG revealed electronegative Schubert-Bornschein configuration in keeping with cCSNB with ON-bipolar cell dysfunction. Patients were lacking pathogenic variants in known genes implicated in IRDs, including CSNB. Two different homozygous pathogenic variants, c.1563_1566del, p.(Val522Glufs*18) and c.1795C>T, p.(Arg599*) in EGFLAM were identified by ES and GS. The corresponding protein is localized in the outer plexiform layer and important for ON-bipolar cell signaling in the retina. CONCLUSION AND RELEVANCE: This case series reports on a gene defect in EGFLAM implicated in human cCSNB. Clinicians should be aware about this association and consider including EGFLAM in diagnostic gene panels for IRDs. This discovery may lead to faster and more accurate diagnosis of cCSNB and genetic counseling, as well as a pathway for developing therapies.

Adolescent↗
PubMed1977

[Phenylalanine-influenced retinal changes in the newborn rat (author's transl)].

Subject of the present study was the retina of rats following intravenous application of L-phenylalanin. The 19 newborn rats received 0.9 mg/g of the substance twice daily from the first to the seventh postnatal day. Depending on the survival time, alterations of ganglion cells, neuropil, and capillaries were found. Pyknotic and necrotic cells in the bipolar and in the ganglion layer occurred. Animals that were treated for a period of five days developed a marked increase of free ribosomes and round particles with a granular matrix of the cytoplasma but without membranes. Also suggesting damage is the increase of the glycogen in the bipolar and the inner granular layer as well as in the nerve cell extensions adjacent to the capillaries. An additional finding is the swelling of processes of the glia and of neuronal cells in the vicinity of the retina vessels. Since newborn rats do not have the blood-brain carrier of adult animals, toxic damage of the cell membranes with intracellular liquid accumulation can be concluded. Our findings suggest that L-phenylalanin can damage the nerve cell substantially and that alterations of the white matter so far described are not the sole basis of phenylketonuria.

Animals↗
PubMed1977

Effects of alcohol on ganglion cell receptive field properties and sensitivity in the frog retina.

Previous results have shown that alcohol has an effect on vision and on the excitability of retinal neurons. Action potentials of single ganglion cells were recorded by microelectrodes in opened and excised eyes from frogs (Rana temporaria L.). Histologically two types of synapses have been described in the retina: conventional synapses and synapses with a ribbon or bar shaped component surrounded by a rather uniform layer of synaptic vesicles. The "ribbon synapses" are presynaptic contacts in receptor and bipolar cells while horizontal and amacrine cells have conventional synapses. Tests with ethanol doses up to 0.2% indicated stronger effects on the conventional synapses than on the ribbon synapses. Alcohol decreased or abolished the lateral inhibition ( inhibitory surround) mediated by the amacrine cells and depressed the signals from the green rods, which apparently are mediated by horizontal cells. Further alcohol decreased the sensitivity of the signals from the completely dark-adapted red rods in the retina, and increased the sensitivity of the cone-mediated responses for class 3 and deviating class 4 cells, when measured against a background light. Alcohol also increased the latency of the response up to 55 msec. depending on the size of the stimulus field.

Animals↗
PubMed1975

Morphological and functional identifications of catfish retinal neurons. I. Classical morphology.

The morphology of the catfish horizontal cells is comparable to that in other fish retinas. The external horizontal cells contact cone receptors and are stellate in shape; the intermediate horizontal cells are even more so and contact rod receptors. The internal horizontal cells constitute the most proximal layer of the inner nuclear layer and may possibly be, in reality, extended processes from the other two horizontal cell types. Bipolar cells resemble those in other teleost retinas: the size and shape of their dendritic tree encompass a continuous spectrum ranging from what is known as the small to the large bipolar cells. The accepted definition of amacrine cells is sufficiently vague to justify our originating a more descriptive and less inferential name for the (axonless) neurons in the inner nuclear layer which radiate processes throughout the inner synaptic layer. These starbust and spaghetti cells vary considerably in the character and extent of their dendritic spread, but correlates exist in other vertebrate retinas. Ganglion cells are found not only in the classical ganglion layer but displaced into the inner nuclear layer as well. Several types can be distinguished on the basis of cell geometry and by the properties of their dendritic tree. Not all of the categorization corresponds with previous descriptions; our findings suggest that some reorganization may be necessary in the accepted classification of cells in the proximal areas of the vertebrate retina. A subtle yet remarkable pattern underlies the entire structure of the catfish retina; there exists a definite gradient of size within a particular class of cells, and of configuration among the subclasses of a specific cell type. It remains to be seen if these morphological spectra bear any functional consequences. The fact that the structure of the catfish retina most closely resembles those of other phylogenetically ancient animals, such as the skate and the dogfish shark, testifies to its primitive organization; morphological and functional mechanisms discernible in this simple system may, therefore, be applicable to the retinas of higher ordered vertebrates.

Animals↗
PubMed1975

Morphological and functional identifications of catfish retinal neurons. II. Morphological identification.

In this study the morphological origins of the responses from the catfish retinal neurons evoked by step inputs were determined by injecting intracellularly a dye, Procion yellow. A method was devised to view the dye-injected neurons in flat mount to study their dendritic expansion; later the same neurons could be sectioned radially to locate the levels of their somata or dendritic expansion. The results of this study show the inherent danger of identifying dye-injected neurons only in a radial or tangential view. Bipolar cells could be identified functionally without any ambiguity by changing widely the stimulus parameters, because the stimulation of their receptive-field center and surround gave rise to responses of opposing polarity. We found no exception to this rule. The neurons in the proximal layers produced a large variety of responses which could not be segregated into two such classes as the amacrine and ganglion cells. In this part II they were classified into three broad categories: neurons giving rise to sustained, transient, and spiking responses. The demarcation among the three types, morphologywise and functionwise, was vague and not well established. The sustained responses were recoreded from the starburst and spaghetti neurons (part I (9)) which correspond to Ramón y Cajal's (2) amacrine cells. The transient responses, whose patterns were largely invariant of the changes in the stimulus parameters, were recorded from a class of neurons with spindle-shaped somata in the INL. We do not know whether they had axons or not, but we will not be surprised if a future study defines them as a class of ganglion cells. Responses with or without spike discharges were recorded from a class of neurons which were identified as ganglion cells. Observations made on a large number of Procion-injected neurons in both flat-mount preparations and radial sections show that finer dendritic arborizations were not seen in the dye-injected neurons although the presence of such branches was proved in the Golgi preparations. Probably this was due to the weak contrast of the Procion-injected cell against the tissue background, rather than the failure of the dye to diffuse into finer branches. We recognize the severe difficulty involved in the traditional approach of identifying a class of neurons based on typical but subjectively selected functional and structural samples. Neurons have to be classified statistically according to their (quantitative) parameters. (cont'd)

Animals↗
PubMed1979

The nonlinear pathway of Y ganglion cells in the cat retina.

Retinal ganglion cells of the Y type in the cat retina produce two different types of response: linear and nonlinear. The nonlinear responses are generated by a separate and independent nonlinear pathway. The functional connectivity in this pathway is analyzed here by comparing the observed second-order frequency responses of Y cells with predictions of a "sandwich model" in which a static nonlinear stage is sandwiched between two linear filters. The model agrees well with the qualitative and quantitative features of the second-order responses. The prefilter in the model may well be the bipolar cells and the nonlinearity and postfilter in the model are probably associated with amacrine cells.

Action Potentials↗
PubMed1976

Transmission of signals from photoreceptors to ganglion cells in the eye of the turtle.

Synaptic transfer between receptors and ganglion cells was studied in the retina of the turtle. In the normal operation of this pathway, signals are relayed across two or more chemical synapses. Previous work indicates that the receptors give graded hyperpolarization to light, and that the bipolar cells also respond with graded potential changes; the ganglion cells give impulses. Injection of weak electrical currents into a single receptor provides an alternative means of activating the pathway. We have used this technique to examine (1) the role of the receptors' hyperpolarization in signal transmission and (2) the sensitivity and temporal properties of the pathway. The response of a ganglion cell evoked by light on the retina can be duplicated by electrically hyperpolarizing a receptor and antagonized by electrical depolarization. This indicates that the hyperpolarization is responsible for regulating the flow of information from the receptors to the second-order retinal cells. The sensitivity of the synaptic path from cones to ganglion cells, determined from electrical stimulation of single receptors, was found to be sufficient to permit detection of about 100 photoisomerizations. Using the same technique, the kinetics of transfer were studied and found to exhibit a delay or integrating process and also a slow differentiation that blocks steady-state transmission. For the path from red-sensitive cones to ganglion cells, the apparent time constant of the delay process was of the order of 75 ms and that of the differentiation, about 100 ms. In the path from rods to ganglion cells, the differentiation was several times slower.

Animals↗
PubMed1976

[Inhibitory mechanisms within the receptive fields of X-and Y-type retinal ganglion cells of the cat (author's transl)].

Two-stages of the inhibitory mechanisms were assumed within the on-center receptive field (RF) of the cat's retinal ganglion cell on the basis of the following two experiments: 1) Effect of background intensity upon the magnitude of the response to the RF-centered spot of stimulus, and 2) the time course of the inhibitory effect when the additional spot of light is presented in the same RF center region. The first stage is an inhibitory feed-back from horizontal cell to the photoreceptor. Both X-and Y-fields have this feed-back route. By this gain control machanisms, the ganglion cell will respond to the intensity ratio of the spot to the background. [corrected] The second stage of inhibitory mechanism in X-field is the feed-back from sustained amacrine cell to the bipolar cell. Above two stages of feed-back mechanism in X-field explain the strong maintained suppressive effect produced by the additional spot of light. On the other hand, the Y-type ganglion cell will recive the inhibitory input via feed-forward path from trannsient amacrine cell. This explains the transient on- and of f-suppressive effects

Animals↗