scholarly journals Short-Time Ocular Ischemia Induces Vascular Endothelial Dysfunction and Ganglion Cell Loss in the Pig Retina

2019 ◽  
Vol 20 (19) ◽  
pp. 4685 ◽  
Author(s):  
Jenia Kouchek Zadeh ◽  
Andreas Garcia-Bardon ◽  
Erik Kristoffer Hartmann ◽  
Norbert Pfeiffer ◽  
Wael Omran ◽  
...  
Keyword(s):  
Ganglion Cell ◽  
Messenger Rna ◽  
Structural Changes ◽  
Ganglion Cells ◽  
Ischemia Reperfusion ◽  
Retinal Ganglion ◽  
Retinal Arteriole ◽  
Retinal Arterioles ◽  
Short Time

Visual impairment and blindness are often caused by retinal ischemia-reperfusion (I/R) injury. We aimed to characterize a new model of I/R in pigs, in which the intraocular pathways were not manipulated by invasive methods on the ocular system. After 12 min of ischemia followed by 20 h of reperfusion, reactivity of retinal arterioles was measured in vitro by video microscopy. Dihydroethidium (DHE) staining, qPCR, immunohistochemistry, quantification of neurons in the retinal ganglion cell layer, and histological examination was performed. Retinal arterioles of I/R-treated pigs displayed marked attenuation in response to the endothelium-dependent vasodilator, bradykinin, compared to sham-treated pigs. DHE staining intensity and messenger RNA levels for HIF-1α, VEGF-A, NOX2, and iNOS were elevated in retinal arterioles following I/R. Immunoreactivity to HIF-1α, VEGF-A, NOX2, and iNOS was enhanced in retinal arteriole endothelium after I/R. Moreover, I/R evoked a substantial decrease in Brn3a-positive retinal ganglion cells and noticeable retinal thickening. In conclusion, the results of the present study demonstrate that short-time ocular ischemia impairs endothelial function and integrity of retinal blood vessels and induces structural changes in the retina. HIF-1α, VEGF-A, iNOS, and NOX2-derived reactive oxygen species appear to be involved in the pathophysiology.

Functional Circuitry for Peripheral Suppression in Mammalian Y-Type Retinal Ganglion Cells

2007 ◽  
Vol 97 (6) ◽  
pp. 4327-4340 ◽  
Author(s):  
Kareem A. Zaghloul ◽  
Michael B. Manookin ◽  
Bart G. Borghuis ◽  
Kwabena Boahen ◽  
Jonathan B. Demb
Keyword(s):  
Receptive Field ◽  
Ganglion Cell ◽  
Voltage Clamp ◽  
Ganglion Cells ◽  
Glutamate Release ◽  
High Spatial Frequency ◽  
Amacrine Cells ◽  
Horizontal Cells ◽  
Retinal Ganglion

A retinal ganglion cell receptive field is made up of an excitatory center and an inhibitory surround. The surround has two components: one driven by horizontal cells at the first synaptic layer and one driven by amacrine cells at the second synaptic layer. Here we characterized how amacrine cells inhibit the center response of on- and off-center Y-type ganglion cells in the in vitro guinea pig retina. A high spatial frequency grating (4–5 cyc/mm), beyond the spatial resolution of horizontal cells, drifted in the ganglion cell receptive field periphery to stimulate amacrine cells. The peripheral grating suppressed the ganglion cell spiking response to a central spot. Suppression of spiking was strongest and observed most consistently in off cells. In intracellular recordings, the grating suppressed the subthreshold membrane potential in two ways: a reduced slope (gain) of the stimulus-response curve by ∼20–30% and, in off cells, a tonic ∼1-mV hyperpolarization. In voltage clamp, the grating increased an inhibitory conductance in all cells and simultaneously decreased an excitatory conductance in off cells. To determine whether center response inhibition was presynaptic or postsynaptic (shunting), we measured center response gain under voltage-clamp and current-clamp conditions. Under both conditions, the peripheral grating reduced center response gain similarly. This result suggests that reduced gain in the ganglion cell subthreshold center response reflects inhibition of presynaptic bipolar terminals. Thus amacrine cells suppressed ganglion cell center response gain primarily by inhibiting bipolar cell glutamate release.

scholarly journals Divisive suppression explains high-precision firing and contrast adaptation in retinal ganglion cells

2016 ◽  
Author(s):  
Yuwei Cui ◽  
Yanbin V. Wang ◽  
Silvia J. H. Park ◽  
Jonathan B. Demb ◽  
Daniel A. Butts
Keyword(s):  
Ganglion Cell ◽  
Visual Processing ◽  
Cell Function ◽  
Temporal Dynamics ◽  
Ganglion Cells ◽  
Mouse Retina ◽  
Retinal Ganglion ◽  
Nonlinear Processing ◽  
Generation Mechanisms

Visual processing depends on specific computations implemented by complex neural circuits. Here, we present a circuit-inspired model of retinal ganglion cell computation, targeted to explain their temporal dynamics and adaptation to contrast. To localize the sources of such processing, we used recordings at the levels of synaptic input and spiking output in the in vitro mouse retina. We found that an ON-Alpha ganglion cell's excitatory synaptic inputs were described by a divisive interaction between excitation and delayed suppression, which explained nonlinear processing already present in ganglion cell inputs. Ganglion cell output was further shaped by spike generation mechanisms. The full model accurately predicted spike responses with unprecedented millisecond precision, and accurately described contrast adaption of the spike train. These results demonstrate how circuit and cell-intrinsic mechanisms interact for ganglion cell function and, more generally, illustrate the power of circuit-inspired modeling of sensory processing.

scholarly journals Divisive suppression explains high-precision firing and contrast adaptation in retinal ganglion cells

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yuwei Cui ◽  
Yanbin V Wang ◽  
Silvia J H Park ◽  
Jonathan B Demb ◽  
Daniel A Butts
Keyword(s):  
Ganglion Cell ◽  
Visual Processing ◽  
Cell Function ◽  
Temporal Dynamics ◽  
Ganglion Cells ◽  
Mouse Retina ◽  
Retinal Ganglion ◽  
Contrast Adaptation ◽  
Generation Mechanisms

Visual processing depends on specific computations implemented by complex neural circuits. Here, we present a circuit-inspired model of retinal ganglion cell computation, targeted to explain their temporal dynamics and adaptation to contrast. To localize the sources of such processing, we used recordings at the levels of synaptic input and spiking output in the in vitro mouse retina. We found that an ON-Alpha ganglion cell's excitatory synaptic inputs were described by a divisive interaction between excitation and delayed suppression, which explained nonlinear processing that was already present in ganglion cell inputs. Ganglion cell output was further shaped by spike generation mechanisms. The full model accurately predicted spike responses with unprecedented millisecond precision, and accurately described contrast adaptation of the spike train. These results demonstrate how circuit and cell-intrinsic mechanisms interact for ganglion cell function and, more generally, illustrate the power of circuit-inspired modeling of sensory processing.

GABA-activated whole-cell currents in isolated retinal ganglion cells

1988 ◽  
Vol 60 (2) ◽  
pp. 381-396 ◽  
Author(s):  
A. T. Ishida ◽  
B. N. Cohen
Keyword(s):  
Ganglion Cell ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Noise Analysis ◽  
Reversal Potential ◽  
Retinal Ganglion ◽  
Gamma Aminobutyric Acid ◽  
Whole Cell

1. We have begun to analyze neurotransmitter-activated conductances in retinal ganglion cells by measuring the response of single voltage-clamped adult goldfish ganglion cells to gamma-aminobutyric acid (GABA). Here we describe 1) our method of identifying ganglion cells in vitro after their dissociation from papain-treated retinas, and 2) the response of these cells to GABA in the tight-seal whole cell configuration of the patch-clamp method (cf. 41) after 1-4 days of primary cell culture. 2. Ganglion cell somata were backfilled in situ by injections of horseradish peroxidase (HRP) into the optic nerve. After dissociation of the retinas containing these cells, HRP reaction product was localized to cells that retained the size, shape, and an intracellular organelle characteristic of ganglion cells in situ. These features enabled us thereafter to identify ganglion cells in vitro without retrograde marker transport. 3. GABA (3-10 microM) elicited inward currents and substantial noise increases in almost all ganglion cells at negative holding potentials. Reversal potential measurements in salines containing different chloride concentrations indicated that GABA produces a chloride-selective conductance increase in ganglion cells. Bicuculline (10 microM) reversibly inhibited ganglion cell GABA responses. Baclofen (10 microM) alone elicited no responses in ganglion cells. 4. Noise analysis of GABA-activated whole cell currents yielded elementary conductance estimates of 16 pS, with a slow time constant of 30 ms plus a faster component of 1-2 ms. No significant voltage dependence of these values was observed between -20 and -80 mV. 5. We have thus devised a means of identifying ganglion cells dissociated from adult retinas, identified GABAA receptors (cf. 16) on these cells, and found that the responses mediated by these receptors resemble those found in other regions of central nervous system (CNS). These results are consistent with the notion that GABA may function as an inhibitory transmitter at synapses on ganglion cells.

Regulation of retinal ganglion cell production by Sonic hedgehog

Development ◽  
2001 ◽  
Vol 128 (6) ◽  
pp. 943-957 ◽  
Author(s):  
X.M. Zhang ◽  
X.J. Yang
Keyword(s):  
Ganglion Cell ◽  
Wave Front ◽  
Retinal Ganglion Cells ◽  
Sonic Hedgehog ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Cell Production ◽  
Differentiation Wave ◽  
Cell Genesis

Previous work has shown that production of retinal ganglion cells is in part regulated by inhibitory factors secreted by ganglion cell themselves; however, the identities of these molecules are not known. Recent studies have demonstrated that the signaling molecule Sonic hedgehog (Shh) secreted by differentiated retinal ganglion cells is required to promote the progression of ganglion cell differentiation wave front and to induce its own expression. We present evidence that Shh signals play a role to negatively regulate ganglion cell genesis behind the differentiation wave front. Higher levels of Shh expression are detected behind the wave front as ganglion cells accumulate, while the Patched 1 receptor of Shh is expressed in adjacent retinal progenitor cells. Retroviral-mediated overexpression of Shh results in reduced ganglion cell proportions in vivo and in vitro. Conversely, inhibiting endogenous Shh activity by anti-Shh antibodies leads to an increased production of ganglion cells. Shh signals modulate ganglion cell production within the normal period of ganglion cell genesis in vitro without significantly affecting cell proliferation or cell death. Moreover, Shh signaling affects progenitor cell specification towards the ganglion cell fate during or soon after their last mitotic cycle. Thus, Shh derived from differentiated ganglion cells serves as a negative regulator behind the differentiation wave front to control ganglion cell genesis from the competent progenitor pool. Based on these results and other recent findings, we propose that Shh signals secreted by early-differentiated retinal neurons play dual roles at distinct concentration thresholds to orchestrate the progression of retinal neurogenic wave and the emergence of new neurons.

scholarly journals Peroxisome Proliferator-Activated Receptor α Activation Protects Retinal Ganglion Cells in Ischemia-Reperfusion Retinas

2021 ◽  
Vol 8 ◽  
Author(s):  
Fei Yao ◽  
Xuan Zhang ◽  
Xueyan Yao ◽  
Xiaohua Ren ◽  
Xiaobo Xia ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Ischemia Reperfusion ◽  
Retinal Cell ◽  
Ganglion Cell Complex ◽  
Peroxisome Proliferator ◽  
Retinal Ganglion ◽  
Fenofibric Acid ◽  
Peroxisome Proliferator Activated Receptor

Background and Objective: Retinal ischemia-reperfusion (IR) leads to massive loss of retinal ganglion cells (RGC) and characterizes several blind-causing ophthalmic diseases. However, the mechanism related to retinal IR is controversial, and a drug that could prevent the RGC loss caused by IR is still lacking. This study aimed to investigate the role of endogenous retinal peroxisome proliferator-activated receptor (PPAR)α and the therapeutic effect of its agonist, fenofibric acid (FA), in IR-related retinopathy.Materials and Methods: Fenofibric acid treatment was applied to the Sprague–Dawley rats with IR and retinal cell line 28 cells with oxygen-glucose deprivation (OGD) (an in vitro model of IR). Western blotting, real-time PCR, and immunofluorescence were used to examine the expression levels of PPARα, glial fibrillary acidic protein (GFAP), and cyclooxygenase-2 (COX2). Hematoxylin and eosin (HE) staining, propidium iodide (PI) staining, retrograde tracing, and flash visual-evoked potential (FVEP) were applied to assess RGC injury and visual function.Results: Retinal IR down-regulated PPARα expression in vitro and in vivo. Peroxisome proliferator-activated receptor α activation by FA promoted survival of RGCs, mitigated thinning of the ganglion cell complex, and decreased the latency of positive waves of FVEPs after IR injury. Further, FA treatment enhanced the expression of endogenous PPARα and suppressed the expression of GFAP and COX2 significantly.Conclusion: Peroxisome proliferator-activated receptor α activation by FA is protective against RGC loss in retinal IR condition, which may occur by restoring PPARα expression, inhibiting activation of glial cells, and suppressing retinal inflammation. All these findings indicate the translational potential of FA in treating IR-related retinopathy.

scholarly journals Otx2 stimulates adult retinal ganglion cell regeneration

2020 ◽  
Author(s):  
Raoul Torero-Ibad ◽  
Nicole Quenech’du ◽  
Alain Prochiantz ◽  
Kenneth L. Moya
Keyword(s):  
Ganglion Cell ◽  
Cell Survival ◽  
Retinal Ganglion Cell ◽  
Ganglion Cells ◽  
Retinal Ganglion ◽  
Response To Stress ◽  
Retinal Ganglion Cell Survival ◽  
The Brain

AbstractRetinal ganglion cell axons provide the only link between the light sensitive and photon transducing neural retina and visual centers of the brain. Retinal ganglion cell axon degeneration occurs in a number of blinding diseases and the ability to stimulate axon regeneration from surviving ganglion cells could provide the anatomic substrate for restoration of vision. OTX2 is a homeoprotein transcription factor expressed in the retina and previous studies showed that, in response to stress, exogenous OTX2 increases the in vitro and in vivo survival of retinal ganglion cells. The present results show that, in addition to promoting adult retinal ganglion cell survival, OTX2 also stimulates the regeneration of their axons in vitro and in vivo. This dual activity of OTX2 on retinal ganglion cell survival and regeneration is of potential interest for degenerative diseases affecting this cell type.

Developmental time course distinguishes changes in spontaneous and light-evoked retinal ganglion cell activity in rd1 and rd10 mice

2011 ◽  
Vol 105 (6) ◽  
pp. 3002-3009 ◽  
Author(s):  
Steven F. Stasheff ◽  
Malini Shankar ◽  
Michael P. Andrews
Keyword(s):  
Ganglion Cell ◽  
Time Course ◽  
Developmental Plasticity ◽  
Ganglion Cells ◽  
Cell Activity ◽  
Retinal Disease ◽  
Developmental Time ◽  
Retinal Ganglion ◽  
Evoked Activity

In a subset of hereditary retinal diseases, early photoreceptor degeneration causes rapidly progressive blindness in children. To better understand how retinal development may interact with degenerative processes, we compared spontaneous and light-evoked activity among retinal ganglion cells in rd1 and rd10 mice, strains with closely related retinal disease. In each, a mutation in the Pde6b gene causes photoreceptor dysfunction and death, but in rd10 mice degeneration starts after a peak in developmental plasticity of retinal circuitry and thereafter progresses more slowly. In vitro multielectrode action potential recordings revealed that spontaneous waves of correlated ganglion cell activity comparable to those in wild-type mice were present in rd1 and rd10 retinas before eye opening [postnatal day (P) 7 to P8]. In both strains, spontaneous firing rates increased by P14–P15 and were many times higher by 4–6 wk of age. Among rd1 ganglion cells, all responses to light had disappeared by ∼P28, yet in rd10 retinas vigorous ON and OFF responses were maintained well beyond this age and were not completely lost until after P60. This difference in developmental time course separates mechanisms underlying the hyperactivity from those that alter light-driven responses in rd10 retinas. Moreover, several broad physiological groups of cells remained identifiable according to response polarity and time course as late as P60. This raises hope that visual function might be preserved or restored despite ganglion cell hyperactivity seen in inherited retinal degenerations, particularly if treatment or manipulation of early developmental plasticity were to be timed appropriately.

scholarly journals A Safe GDNF and GDNF/BDNF Controlled Delivery System Improves Migration in Human Retinal Pigment Epithelial Cells and Survival in Retinal Ganglion Cells: Potential Usefulness in Degenerative Retinal Pathologies

2021 ◽  
Vol 14 (1) ◽  
pp. 50
Author(s):  
Alicia Arranz-Romera ◽  
Maria Hernandez ◽  
Patricia Checa-Casalengua ◽  
Alfredo Garcia-Layana ◽  
Irene T. Molina-Martinez ◽  
...  
Keyword(s):  
Cell Viability ◽  
Retinal Ganglion Cells ◽  
Neurotrophic Factor ◽  
Retinal Pigment Epithelial ◽  
Ganglion Cells ◽  
Retinal Pigment ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Retinal Ganglion ◽  
Pigment Epithelial

We assessed the sustained delivery effect of poly (lactic-co-glycolic) acid (PLGA)/vitamin E (VitE) microspheres (MSs) loaded with glial cell-derived neurotrophic factor (GDNF) alone (GDNF-MSs) or combined with brain-derived neurotrophic factor (BDNF; GDNF/BDNF-MSs) on migration of the human adult retinal pigment epithelial cell-line-19 (ARPE-19) cells, primate choroidal endothelial (RF/6A) cells, and the survival of isolated mouse retinal ganglion cells (RGCs). The morphology of the MSs, particle size, and encapsulation efficiencies of the active substances were evaluated. In vitro release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability, terminal deoxynucleotidyl transferase (TdT) deoxyuridine dUTP nick-end labelling (TUNEL) apoptosis, functional wound healing migration (ARPE-19; migration), and (RF/6A; angiogenesis) assays were conducted. The safety of MS intravitreal injection was assessed using hematoxylin and eosin, neuronal nuclei (NeuN) immunolabeling, and TUNEL assays, and RGC in vitro survival was analyzed. MSs delivered GDNF and co-delivered GDNF/BDNF in a sustained manner over 77 days. The BDNF/GDNF combination increased RPE cell migration, whereas no effect was observed on RF/6A. MSs did not alter cell viability, apoptosis was absent in vitro, and RGCs survived in vitro for seven weeks. In mice, retinal toxicity and apoptosis was absent in histologic sections. This delivery strategy could be useful as a potential co-therapy in retinal degenerations and glaucoma, in line with future personalized long-term intravitreal treatment as different amounts (doses) of microparticles can be administered according to patients’ needs.

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