scholarly journals Ocular hypertension drives remodeling of AMPA receptors in select populations of retinal ganglion cells

2019 ◽  
Author(s):  
Asia L. Sladek ◽  
Scott Nawy
Keyword(s):  
Retinal Ganglion Cells ◽  
Ampa Receptors ◽  
Ganglion Cells ◽  
Synaptic Activity ◽  
Retinal Ganglion ◽  
Degenerative Diseases ◽  
Aberrant Expression ◽  
Pathological Conditions ◽  
Cb1 Antagonist ◽  
Genomic Editing

AbstractAMPA receptors in the CNS are normally impermeable to Ca2+ but aberrant expression of Ca2+-permeable AMPA receptors (CP-AMPARs) occurs in pathological conditions such as ischemia or epilepsy, or in degenerative diseases such as ALS. Here we show that select populations of retinal ganglion cells (RGCs) similarly express high levels of CP-AMPARs in a mouse model of glaucoma. CP-AMPAR expression increased dramatically in both α On and α transient Off RGCs, and this increase was prevented by genomic editing of the GluA2 Q/R site. α On RGCs with elevated CP-AMPAR levels displayed profound synaptic depression, which was reduced by selectively blocking CP-AMPARs, buffering Ca2+ with BAPTA, or with the CB1 antagonist AM251, suggesting that depression was mediated by a retrograde transmitter which might be triggered by influx of Ca2+ through CP-AMPARs. Thus OHT alters the composition of AMPARs and modulates patterns of synaptic activity in select populations of RGCs.

scholarly journals on and off Channels of the Frog Optic Tectum Revealed by Current Source Density Analysis

1998 ◽  
Vol 80 (4) ◽  
pp. 1886-1899 ◽  
Author(s):  
Hideki Nakagawa ◽  
Nobuyoshi Matsumoto
Keyword(s):  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Current Source ◽  
Current Source Density ◽  
Synaptic Activity ◽  
Diffuse Light ◽  
Retinal Ganglion ◽  
Source Density ◽  
Current Source Density Analysis ◽  
Density Analysis

Nakagawa, Hideki and Nobuyoshi Matsumoto. on and off channels of the frog optic tectum revealed by current source density analysis. J. Neurophysiol. 80: 1886–1899, 1998. The spatiotemporal patterns of excitatory synaptic activity in response to diffuse light on and off stimuli were examined by means of current source density (CSD) analysis. The qualitative and quantitative analyses obtained from 24 depth profiles for each stimulus revealed obviously different distributions of synaptic activity in the laminar structure. Two or three dominant current sinks I, II, and III were evoked in response to diffuse light on stimulation. Sink I was observed at the bottom of the retinorecipient layer. Both sinks II and III, showing an identical spatial pattern, were observed just above sink I. On the other hand, diffuse light off stimulation elicited up to six current sinks IV, V, VI, VII, VIII, and IX. Sink IV was observed at the bottom of the retinorecipient layer. Sink V was observed in the most superficial layer. Both sinks VI and VIII were located between the two preceding sinks. Finally, sinks VII and IX occurred below the retinorecipient layer. Five electrically evoked current sinks A, B, C, D, and E, characterized in our previous study, were also recognized in the present quantitative analysis. A statistical analysis revealed that, in visually evoked responses, statistical differences in the spatial distribution were not present between sinks I and IV, and sinks II and VIII ( P < 0.05). The analysis also showed that, in electrically evoked responses, only a pair of sinks C and E exhibit virtually identical spatial distribution ( P < 0.05). Based on well-known properties of the retinal ganglion cells, possible neuronal mechanisms underlying each of current sinks in the on and off channels and their functional meanings were considered. Sink I reflects the excitatory monosynaptic activity derived from R3 retinal ganglion cells. Sink IV reflects the excitatory monosynaptic activity derived from both R3 and R4 cells. Sinks V, VI, VII, and IX may be composed of successive polysynaptic excitatory potentials derived from convergence of inputs from both R3 and R4 cells. We concluded that the early four sinks play in particular an important role in eliciting avoidance behavior. On the other hand, sinks II, III, and VIII reflect excitatory synaptic activities derived from on-off retinal fibers of another type having slow conduction velocity. These late current sinks were suggested to mediate prey catching and its facilitation.

Analysis of Excitatory and Inhibitory Spontaneous Synaptic Activity in Mouse Retinal Ganglion Cells

1998 ◽  
Vol 80 (3) ◽  
pp. 1327-1340 ◽  
Author(s):  
Ning Tian ◽  
Thomas N. Hwang ◽  
David R. Copenhagen
Keyword(s):  
Retinal Ganglion Cells ◽  
Time Constant ◽  
Decay Time ◽  
Ganglion Cells ◽  
Glycine Receptor ◽  
Synaptic Activity ◽  
Decay Time Constant ◽  
Retinal Ganglion ◽  
Synaptic Inputs ◽  
Perforated Patch

Tian, Ning, Thomas N. Hwang, and David R. Copenhagen. Analysis of excitatory and inhibitory spontaneous synaptic activity in mouse retinal ganglion cells. J. Neurophysiol. 80: 1327–1340, 1998. Spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs) were identified and characterized with whole cell and perforated patch voltage-clamp recordings in adult mouse retinal ganglion cells. Pharmacological dissection revealed that all cells were driven by spontaneous synaptic inputs mediated by glutamate and γ-aminobutyric acid-A (GABAA) receptors. One-half (7/14) of the cells also received glycinergic spontaneous synaptic inputs. Both GABAA and glycine receptor–mediated sIPSCs had rise times (10–90%) of <1 ms. The decay times of the GABAA receptor–mediated sIPSCs were comparable with those of the glycine receptor–mediated sIPSCs. The average decay time constant for monoexponentially fitted sIPSCs was 63.2 ± 74.1 ms (mean ± SD, n = 3278). Glutamate receptor–mediated sEPSCs had an average rise time of 0.50 ± 0.20 ms ( n = 109) and an average monoexponential decay time constant of 5.9 ± 8.6 ms ( n = 2705). Slightly more than two-thirds of the spontaneous synaptic events were monoexponential (68% for sIPSCs and 76% for sEPSCs). The remainder of the events was biexponential. The amplitudes of the spontaneous synaptic events were not correlated with rise times, suggesting that the electrotonic filtering properties of the neurons and/or differences in the spatial location of synaptic inputs could not account for the difference between the decay time constants of the glutamate and GABAA/glycine receptor–mediated spontaneous synaptic events. The amplitudes of sEPSCs were similar to those recorded in tetrodotoxin (TTX), consistent with the events measured in control saline being the response to the release of a single quantum of transmitter. The range of the sIPSC amplitudes in control saline was wider than that recorded in TTX, consistent with some sIPSCs being evoked by presynaptic spikes having an average quantal size greater than one. The rates of sIPSCs and sEPSCs were determined under equivalent conditions by recording with perforated patch electrodes at potentials at which both types of event could be identified. Two groups of ganglion cell were observed; one group had an average sEPSCs/sIPSCs frequency ratio of 0.96 ± 0.77 ( n = 28) and another group had an average ratio of 6.63 ± 0.82 ( n = 7). These findings suggest that a subset of cells is driven much more strongly by excitatory synaptic inputs. We propose that this subset of cells could be off ganglion cells, consistent with the higher frequency of spontaneous action potentials found in off ganglion cells in other studies.

scholarly journals Glutamate Stimulation Dysregulates AMPA Receptors-Induced Signal Transduction Pathway in Leber’s Inherited Optic Neuropathy Patient-Specific hiPSC-Derived Retinal Ganglion Cells

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 625
Author(s):  
Yang ◽  
Nguyen ◽  
Lin ◽  
Yarmishyn ◽  
Chen ◽  
...  
Keyword(s):  
Retinal Ganglion Cells ◽  
Optic Neuropathy ◽  
Ampa Receptors ◽  
Ganglion Cells ◽  
Genetic Disorder ◽  
Signal Transduction Pathway ◽  
Cellular Level ◽  
Scaffold Proteins ◽  
Patient Specific ◽  
Retinal Ganglion

The mitochondrial genetic disorder, Leber’s hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise mechanisms of LHON disease penetrance and progression are not completely elucidated. Human-induced pluripotent stem cells (hiPSCs) offer unique opportunities to investigate disease-relevant phenotypes and regulatory mechanisms underlying LHON pathogenesis at the cellular level. In this study, we successfully generated RGCs by differentiation of LHON patient-specific hiPSCs. We modified the protocol of differentiation to obtain a more enriched population of single-cell RGCs for LHON study. Based on assessing morphology, expression of specific markers and electrophysiological activity, we found that LHON-specific hiPSC-derived were more defective in comparison with normal wild-type RGCs. Based on our previous study, whereby by using microarray analysis we identified that the components of glutamatergic synapse signaling pathway were significantly downregulated in LHON-specific RGCs, we focused our study on glutamate-associated α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. We found that the protein expression levels of the subunits of the AMPA receptor, GluR1 and GluR2, and their associated scaffold proteins were decreased in LHON-RGCs. By performing the co-immunoprecipitation assay, we found several differences in the efficiencies of interaction between AMPA subunits and scaffold proteins between normal and LHON-specific RGCs.

Cannabinoids modulate spontaneous synaptic activity in retinal ganglion cells

2011 ◽  
Vol 28 (5) ◽  
pp. 393-402 ◽  
Author(s):  
T. P. MIDDLETON ◽  
D. A. PROTTI
Keyword(s):  
Synaptic Transmission ◽  
Retinal Ganglion Cells ◽  
Cannabinoid Receptor ◽  
Ganglion Cells ◽  
Cell Voltage ◽  
Receptor Activation ◽  
Synaptic Activity ◽  
Retinal Cell ◽  
Retinal Ganglion ◽  
Retinal Processing

AbstractThe endocannabinoid (ECB) system has been found throughout the central nervous system and modulates cell excitability in various forms of short-term plasticity. ECBs and their receptors have also been localized to all retinal cells, and cannabinoid receptor activation has been shown to alter voltage-dependent conductances in several different retinal cell types, suggesting a possible role for cannabinoids in retinal processing. Their effects on synaptic transmission in the mammalian retina, however, have not been previously investigated. Here, we show that exogenous cannabinoids alter spontaneous synaptic transmission onto retinal ganglion cells (RGCs). Using whole-cell voltage-clamp recordings in whole-mount retinas, we measured spontaneous postsynaptic currents (SPSCs) in RGCs in adult and young (P14–P21) mice. We found that the addition of an exogenous cannabinoid agonist, WIN55212-2 (5 μM), caused a significant reversible reduction in the frequency of SPSCs. This change, however, did not alter the kinetics of the SPSCs, indicating a presynaptic locus of action. Using blockers to isolate inhibitory or excitatory currents, we found that cannabinoids significantly reduced the release probability of both GABA and glutamate, respectively. While the addition of cannabinoids reduced the frequency of both GABAergic and glutamatergic SPSCs in both young and adult mice, we found that the largest effect was on GABA-mediated currents in young mice. These results suggest that the ECB system may potentially be involved in the modulation of signal transmission in the retina. Furthermore, they suggest that it might play a role in the developmental maturation of synaptic circuits, and that exogenous cannabinoids are likely able to disrupt retinal processing and consequently alter vision.

scholarly journals NMDA and AMPA receptors contribute similarly to temporal processing in mammalian retinal ganglion cells

2014 ◽  
Vol 592 (22) ◽  
pp. 4877-4889 ◽  
Author(s):  
Benjamin K. Stafford ◽  
Michael B. Manookin ◽  
Joshua H. Singer ◽  
Jonathan B. Demb
Keyword(s):  
Retinal Ganglion Cells ◽  
Ampa Receptors ◽  
Temporal Processing ◽  
Ganglion Cells ◽  
Retinal Ganglion
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