Biology subjects

Vinberg, F.

Publications and source records attributed to Vinberg, F..

6 recordsLinked to original sources

bioRxiv2025

Downregulation of Transducin Delays Photoreceptor Degeneration in P23H Rhodopsin Retinitis Pigmentosa

In inherited blinding diseases, such as Retinitis Pigmentosa (RP), photoreceptors progressively degenerate, eventually leading to blindness. Unfortunately, effective treatments to prevent or delay vision loss do not exist for most RPs. Dark rearing is known to delay retinal degeneration in preclinical models of RP. Therefore, in this study we evaluated the impact of reducing photoreceptor light signaling on RP progression. This was done by genetically ablating or downregulating transducin in rods or cones in a preclinical RP model carrying a single P23H mutant rhodopsin allele (P23H mice). Ablating rod transducin significantly improved photoreceptor survival in the P23H retina. Additionally, downregulating rod transducin promoted photoreceptor survival and improved rod light response in P23H mice. Remarkably, male P23H mice retained robust cone function until old age in the absence of rod transducin whereas female P23H carriers experienced significantly faster loss of cone function. In these females, reducing cone transducin improved cone function whereas the same treatment was not effective in male P23H carriers. Our data demonstrate that reducing rod or cone transducin expression in P23H mice improves the survival and function of rods and cones, and suggest transducin downregulation as an effective therapeutic strategy to delay photoreceptor degeneration in RP.

physiology↗

bioRxiv2024

Restoring and sustaining human postmortem retinal light responses with scalable methods for testing degenerative disease therapies

Neuro- and retinal degenerative diseases, including Alzheimers, age-related macular degeneration, stroke, and central retinal artery occlusion, rob millions of their independence. Studying these diseases in human retinas has been hindered by the immediate loss of neuronal activity postmortem. While recent studies restored limited activity in postmortem CNS tissues, synchronized neuronal transmission >30 minutes postmortem remained elusive. Our study overcomes this barrier by reviving and sustaining light signal transmission in human retinas recovered up to four hours and stored 48 hours postmortem. We also establish infrared-based ex vivo imaging for precise sampling, a closed perfusion system for drug testing, and an ex vivo ischemia-reperfusion model in mouse and human retina. This platform enables testing of neuroprotective and neurotoxic effects of drugs targeting oxidative stress and glutamate excitotoxicity. Our advances question the irreversibility of ischemic injury, support preclinical vision restoration studies, offer new insights into treating ischemic CNS injuries, and pave the way for transplantation of human donor eyes. TeaserReviving light signaling in postmortem human retinas challenges the irreversibility of ischemic injury and advances research to restore vision.

neuroscience↗

bioRxiv2020

Revival of light-evoked neuronal signals in the post-mortem mammalian and human retina

The retina, a highly metabolic tissue in the central nervous system, consumes the most oxygen and energy stores in the body by tissue mass/volume. Consequently, it is not surprising that retinal ischemia leads to a rapid loss of retinal light responses and electrical transmission. In this study, we show that despite a swift decline of retinal light responses after circulatory death (decay time constant {tau} = [~]1-2 min), we were able to restore mouse rod and cone photoreceptor light signals from enucleated eyes up to 3 h postmortem with significantly better postmortem recovery of cone versus rod light responses. We also demonstrate that both rod and cone phototransduction are more resistant to postmortem enucleation delay than synaptic transmission to second order neurons (bipolar cells). Encouraged by these analyses and the lack of previously successful postmortem retinal light recordings from human foveal/macular photoreceptors, we attempted to restore light responses in the human macula using donor eyes harvested 0.5 - 5 hours postmortem. Here we show successful recordings of human macular cone photoresponses in samples obtained from eyes enucleated up to 5 hours postmortem. Comparing freshly enucleated non-human primate eyes with human eyes enucleated and reoxygenated at different times after death, we show the exponential decay of the light response amplitudes has a time constant of 74 min. We find that both cause of death and donor age are useful parameters for predicting the recovery of retinal light responses in postmortem human macular tissue. Moreover, we present evidence that hypoxia and secondary acidosis, two modifiable factors, are primary contributors to the rapid loss of retinal light signaling after death. Finally, we show postmortem hypoxia rather than acidosis is the major cause of irreversible decay of the light response amplitudes. The criteria and methodology that we have established here for reviving electrical photoresponses in the postmortem human eye will serve as a new starting point for studying neurophysiology and disease in the human retina.

neuroscience↗

bioRxiv2020

Homeostatic plasticity triggered by rod photoreceptor degenerative disease is associated with maintenance of sensitive night vision

Neuronal plasticity of the inner retina has been observed in response to photoreceptor degeneration. Typically, this phenomenon has been considered maladaptive and may preclude vision restoration in the blind. However, several recent studies utilizing triggered photoreceptor ablation have shown adaptive responses in bipolar cell dendrites expected to support normal vision. Whether such homeostatic plasticity occurs during progressive photoreceptor degenerative disease to help maintain normal visual behavior is unknown. We addressed these issues in an established mouse model of Retinitis Pigmentosa caused by the P23H mutation in rhodopsin. We show robust modulation of the retinal transcriptomic network reminiscent of the neurodevelopmental state as well as potentiation of rod - rod bipolar cell signaling following rod photoreceptor degeneration. Additionally, we found highly sensitive night vision in P23H mice even when more than half of the rod photoreceptors were lost. The results implicate retinal adaptation leading to persistent visual function during photoreceptor degenerative disease.

neuroscience↗

bioRxiv2020

Rod phototransduction and light signal transmission during type 2 diabetes

ObjectiveDiabetic retinopathy is a major complication of diabetes recently associated with compromised photoreceptor function. Multiple stressors in diabetes, such as hyperglycemia, oxidative stress and inflammatory factors, have been identified, but systemic effects of diabetes on outer retina function are incompletely understood. We assessed photoreceptor physiology in vivo and in isolated retinas to better understand how alterations in the cellular environment compared to intrinsic cellular/molecular properties of the photoreceptors, affect light signal transduction and transmission in the retina in chronic type 2 diabetes. Research Design and MethodsPhotoreceptor function was assessed in BKS.Cs-Dock7m +/+ Lepr db/J mice, using homozygotes for Leprdb as a model of type 2 diabetes and heterozygotes as non-diabetic controls. In vivo electroretinogram (ERG) was recorded in dark adapted mice at both 3 and 6 months of age. For ex vivo ERG, isolated retinas were superfused with oxygenated Ames media supplemented with 30 mM glucose or mannitol as iso-osmotic control and electrical responses to light stimuli were recorded. ResultsWe found that both transduction and transmission of light signals by rod photoreceptors were compromised in 6 month old (n=9-10 eyes from 5 animals,*** p<001) but not in 3 month old diabetic mice in vivo (n=4-8 eyes from 2-4 animals). In contrast, rod signaling was similar in isolated retinas from 6 month old control and diabetic mice under normoglycemic conditions (n=11). Acutely elevated glucose ex vivo increased light-evoked rod photoreceptor responses in control mice (n=11, *** p<0.001), but did not affect light responses in diabetic mice (n=11). ConclusionsOur data suggest that long-term diabetes does not irreversibly change the ability of rod photoreceptors to transduce and mediate light signals. However, type 2 diabetes appears to induce adaptational changes in the rods that render them less sensitive to increased availability of glucose. Significance of this studyO_ST_ABSWhat is already known about this subject?C_ST_ABSRetinal neuronal dysfunction in diabetic retinopathy frequently precedes microvascular changes. Damage to photoreceptors has been reported, although the literature is not entirely conclusive, and the underlying mechanisms and reversibility of photoreceptor dysfunction in diabetes remain unknown. What are the new findings?We confirm that retinal function is impaired in vivo in diabetic mice, but report normal function of the isolated diabetic retina under optimal physiological conditions. However, elevated glucose concentrations augment photoreceptor function in the isolated non-diabetic retina, whereas this response is impaired by long-term diabetes. How might these results change the focus of research or clinical practice?Our results clarify that photoreceptor function is not irreversibly damaged and that systemic factors may suppress photoreceptor function in diabetic mice in vivo. The consequences of altered glucose handling in long-term diabetic photoreceptors remain to be evaluated.

neuroscience↗

bioRxiv2019

Mitochondrial Ca2+ influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

Mitochondrial Ca2+ regulates key cellular processes including cytosolic Ca2+ signals, energy production, and susceptibility to apoptosis. Photoreceptors are specialized neurons that have extraordinarily high energy demands and rely on cytosolic Ca2+ signals for light adaptation and neurotransmission. Here we show that unlike other neurons zebrafish cone photoreceptors express low levels of the mitochondrial Ca2+ uniporter (MCU), the channel that allows mitochondrial Ca2+ entry. To determine why MCU expression is kept low, we overexpressed MCU specifically in cones. This increases mitochondrial [Ca2+], causes faster cytosolic Ca2+ clearance, and accelerates photoresponse recovery. Moreover, flux through the citric acid cycle increases despite dramatic changes in mitochondrial ultrastructure and localization. Remarkably, cones survive this ongoing stress until late adulthood. Our findings demonstrate the importance of tuning mitochondrial Ca2+ influx to modulate physiological and metabolic processes and reveal a novel directed movement of abnormal mitochondria in photoreceptors.

cell biology↗