49 results on '"Lukasiewicz PD"'
Search Results
2. Evidence for glycine modulation of excitatory synaptic inputs to retinal ganglion cells
- Author
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Lukasiewicz, PD, primary and Roeder, RC, additional
- Published
- 1995
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3. A novel GABA receptor modulates synaptic transmission from bipolar to ganglion and amacrine cells in the tiger salamander retina
- Author
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Lukasiewicz, PD, primary and Werblin, FS, additional
- Published
- 1994
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4. A novel GABA receptor on bipolar cell terminals in the tiger salamander retina
- Author
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Lukasiewicz, PD, primary, Maple, BR, additional, and Werblin, FS, additional
- Published
- 1994
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5. The spatial distribution of excitatory and inhibitory inputs to ganglion cell dendrites in the tiger salamander retina
- Author
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Lukasiewicz, PD, primary and Werblin, FS, additional
- Published
- 1990
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6. Light-evoked glutamate transporter EAAT5 activation coordinates with conventional feedback inhibition to control rod bipolar cell output.
- Author
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Bligard GW, DeBrecht J, Smith RG, and Lukasiewicz PD
- Subjects
- Animals, Female, Glycine metabolism, Male, Mice, Mice, Inbred C57BL, Patch-Clamp Techniques, gamma-Aminobutyric Acid metabolism, Excitatory Amino Acid Transporter 5 metabolism, Feedback, Physiological physiology, Glutamic Acid metabolism, Neural Inhibition physiology, Retinal Bipolar Cells physiology, Retinal Rod Photoreceptor Cells physiology, Signal Transduction physiology
- Abstract
In the retina, modulation of the amplitude of dim visual signals primarily occurs at axon terminals of rod bipolar cells (RBCs). GABA and glycine inhibitory neurotransmitter receptors and the excitatory amino acid transporter 5 (EAAT5) modulate the RBC output. EAATs clear glutamate from the synapse, but they also have a glutamate-gated chloride conductance. EAAT5 acts primarily as an inhibitory glutamate-gated chloride channel. The relative role of visually evoked EAAT5 inhibition compared with GABA and glycine inhibition has not been addressed. In this study, we determine the contribution of EAAT5-mediated inhibition onto RBCs in response to light stimuli in mouse retinal slices. We find differences and similarities in the two forms of inhibition. Our results show that GABA and glycine mediate nearly all lateral inhibition onto RBCs, as EAAT5 is solely a mediator of RBC feedback inhibition. We also find that EAAT5 and conventional GABA inhibition both contribute to feedback inhibition at all stimulus intensities. Finally, our in silico modeling compares and contrasts EAAT5-mediated to GABA- and glycine-mediated feedback inhibition. Both forms of inhibition have a substantial impact on synaptic transmission to the postsynaptic AII amacrine cell. Our results suggest that the late phase EAAT5 inhibition acts with the early phase conventional, reciprocal GABA inhibition to modulate the rod signaling pathway between rod bipolar cells and their downstream synaptic targets. NEW & NOTEWORTHY Excitatory amino acid transporter 5 (EAAT5) glutamate transporters have a chloride channel that is strongly activated by glutamate, which modulates excitatory signaling. We found that EAAT5 is a major contributor to feedback inhibition on rod bipolar cells. Inhibition to rod bipolar cells is also mediated by GABA and glycine. GABA and glycine mediate the early phase of feedback inhibition, and EAAT5 mediates a more delayed inhibition. Together, inhibitory transmitters and EAAT5 coordinate to mediate feedback inhibition, controlling neuronal output.
- Published
- 2020
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7. Differential encoding of spatial information among retinal on cone bipolar cells.
- Author
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Purgert RJ and Lukasiewicz PD
- Subjects
- Amacrine Cells physiology, Animals, Axons physiology, Male, Mice, Mice, Inbred C57BL, Neural Inhibition, Retinal Bipolar Cells physiology, Retinal Cone Photoreceptor Cells physiology, Space Perception
- Abstract
The retina is the first stage of visual processing. It encodes elemental features of visual scenes. Distinct cone bipolar cells provide the substrate for this to occur. They encode visual information, such as color and luminance, a principle known as parallel processing. Few studies have directly examined whether different forms of spatial information are processed in parallel among cone bipolar cells. To address this issue, we examined the spatial information encoded by mouse ON cone bipolar cells, the subpopulation excited by increments in illumination. Two types of spatial processing were identified. We found that ON cone bipolar cells with axons ramifying in the central inner plexiform layer were tuned to preferentially encode small stimuli. By contrast, ON cone bipolar cells with axons ramifying in the proximal inner plexiform layer, nearest the ganglion cell layer, were tuned to encode both small and large stimuli. This dichotomy in spatial tuning is attributable to amacrine cells providing stronger inhibition to central ON cone bipolar cells compared with proximal ON cone bipolar cells. Furthermore, background illumination altered this difference in spatial tuning. It became less pronounced in bright light, as amacrine cell-driven inhibition became pervasive among all ON cone bipolar cells. These results suggest that differential amacrine cell input determined the distinct spatial encoding properties among ON cone bipolar cells. These findings enhance the known parallel processing capacity of the retina., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
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8. Developmental regulation and activity-dependent maintenance of GABAergic presynaptic inhibition onto rod bipolar cell axonal terminals.
- Author
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Schubert T, Hoon M, Euler T, Lukasiewicz PD, and Wong RO
- Subjects
- Action Potentials drug effects, Action Potentials genetics, Age Factors, Animals, Animals, Newborn, Carrier Proteins metabolism, Excitatory Amino Acid Agonists pharmacology, Gene Expression Regulation, Developmental genetics, Glutamate Decarboxylase genetics, Glutamic Acid, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Transmission, Mutation genetics, Nerve Net drug effects, Nerve Net metabolism, Nerve Tissue Proteins metabolism, Neural Inhibition drug effects, Neural Inhibition genetics, Patch-Clamp Techniques, Presynaptic Terminals ultrastructure, Protein Kinase C metabolism, Receptors, GABA-A metabolism, Receptors, Glutamate metabolism, Receptors, Glycine, Retina cytology, Retinal Bipolar Cells drug effects, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid pharmacology, Gene Expression Regulation, Developmental physiology, Neural Inhibition physiology, Presynaptic Terminals physiology, Retinal Bipolar Cells physiology
- Abstract
Presynaptic inhibition onto axons regulates neuronal output, but how such inhibitory synapses develop and are maintained in vivo remains unclear. Axon terminals of glutamatergic retinal rod bipolar cells (RBCs) receive GABAA and GABAC receptor-mediated synaptic inhibition. We found that perturbing GABAergic or glutamatergic neurotransmission does not prevent GABAergic synaptogenesis onto RBC axons. But, GABA release is necessary for maintaining axonal GABA receptors. This activity-dependent process is receptor subtype specific: GABAC receptors are maintained, whereas GABAA receptors containing α1, but not α3, subunits decrease over time in mice with deficient GABA synthesis. GABAA receptor distribution on RBC axons is unaffected in GABAC receptor knockout mice. Thus, GABAA and GABAC receptor maintenance are regulated separately. Although immature RBCs elevate their glutamate release when GABA synthesis is impaired, homeostatic mechanisms ensure that the RBC output operates within its normal range after eye opening, perhaps to regain proper visual processing within the scotopic pathway., (Copyright © 2013 Elsevier Inc. All rights reserved.)
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- 2013
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9. The mode of retinal presynaptic inhibition switches with light intensity.
- Author
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Ichinose T and Lukasiewicz PD
- Subjects
- Animals, Exocytosis physiology, Female, Glutamate Plasma Membrane Transport Proteins antagonists & inhibitors, In Vitro Techniques, Male, Membrane Potentials drug effects, Mice, Mice, Inbred C57BL, Neural Inhibition drug effects, Presynaptic Terminals drug effects, Presynaptic Terminals physiology, Retinal Bipolar Cells drug effects, Retinal Rod Photoreceptor Cells drug effects, Synaptic Transmission drug effects, Glutamate Plasma Membrane Transport Proteins physiology, Light, Membrane Potentials physiology, Neural Inhibition physiology, Retinal Bipolar Cells physiology, Retinal Rod Photoreceptor Cells physiology, Synaptic Transmission physiology
- Abstract
Excitatory amino acid transporters (EAATs) terminate signaling in the CNS by clearing released glutamate. Glutamate also evokes an EAAT-mediated Cl(-) current, but its role in CNS signaling is poorly understood. We show in mouse retina that EAAT-mediated Cl(-) currents that were evoked by light inhibit rod pathway signaling. EAATs reside on rod bipolar cell axon terminals where GABA and glycine receptors also mediate light-evoked inhibition. We found that the mode of inhibition depended on light intensity. Dim light evoked GABAergic and glycinergic inhibition with rapid kinetics and a large spatial extent. Bright light evoked predominantly EAAT-mediated inhibition with slow kinetics and a small spatial extent. The switch to EAAT-mediated signaling in bright light supplements receptor-mediated signaling to expand the dynamic range of inhibition and contributes to the transition from rod to cone signaling by suppressing rod pathway signaling in bright light conditions.
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- 2012
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10. Amacrine cells: seeing the forest and the trees.
- Author
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Diamond JS and Lukasiewicz PD
- Subjects
- Animals, Humans, Amacrine Cells physiology, Retina cytology, Vision, Ocular physiology
- Published
- 2012
- Full Text
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11. Nonlinear interactions between excitatory and inhibitory retinal synapses control visual output.
- Author
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Sagdullaev BT, Eggers ED, Purgert R, and Lukasiewicz PD
- Subjects
- 6-Cyano-7-nitroquinoxaline-2,3-dione pharmacology, Animals, Benzodiazepines pharmacology, Electric Stimulation methods, Excitatory Amino Acid Antagonists pharmacology, GABA Antagonists pharmacology, In Vitro Techniques, Mice, Neural Inhibition drug effects, Patch-Clamp Techniques, Phosphinic Acids pharmacology, Photic Stimulation methods, Presynaptic Terminals drug effects, Presynaptic Terminals physiology, Pyridines pharmacology, Retinal Bipolar Cells drug effects, Retinal Bipolar Cells physiology, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells physiology, Synapses drug effects, Synaptic Transmission drug effects, Synaptic Transmission physiology, Neural Inhibition physiology, Nonlinear Dynamics, Retina cytology, Synapses physiology
- Abstract
The visual system is highly sensitive to dynamic features in the visual scene. However, it is not known how or where this enhanced sensitivity first occurs. We investigated this phenomenon by studying interactions between excitatory and inhibitory synapses in the second synaptic layer of the mouse retina. We found that these interactions showed activity-dependent changes that enhanced signaling of dynamic stimuli. Excitatory signaling from cone bipolar cells to ganglion cells exhibited strong synaptic depression, attributable to reduced glutamate release from bipolar cells. This depression was relieved by amacrine cell inhibitory feedback that activated presynaptic GABA(C) receptors. We found that the balance between excitation and feedback inhibition depended on stimulus frequency; at short interstimulus intervals, excitation was enhanced, attributable to reduced inhibitory feedback. This dynamic interplay may enrich visual processing by enhancing retinal responses to closely spaced temporal events, representing rapid changes in the visual environment.
- Published
- 2011
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12. G-protein betagamma-complex is crucial for efficient signal amplification in vision.
- Author
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Kolesnikov AV, Rikimaru L, Hennig AK, Lukasiewicz PD, Fliesler SJ, Govardovskii VI, Kefalov VJ, and Kisselev OG
- Subjects
- Animals, Choice Behavior physiology, Female, GTP-Binding Protein alpha Subunits metabolism, GTP-Binding Protein beta Subunits metabolism, GTP-Binding Protein gamma Subunits metabolism, Male, Mice, Mice, Knockout, Night Vision genetics, Photic Stimulation, Retina anatomy & histology, Retina metabolism, Retina physiology, Retina ultrastructure, Retinal Rod Photoreceptor Cells metabolism, Signal Transduction genetics, Transducin metabolism, Vision, Ocular genetics, Visual Perception genetics, GTP-Binding Protein beta Subunits genetics, GTP-Binding Protein beta Subunits physiology, GTP-Binding Protein gamma Subunits genetics, GTP-Binding Protein gamma Subunits physiology, Models, Statistical, Night Vision physiology, Retinal Rod Photoreceptor Cells physiology, Signal Transduction physiology, Vision, Ocular physiology, Visual Perception physiology
- Abstract
A fundamental question of cell signaling biology is how faint external signals produce robust physiological responses. One universal mechanism relies on signal amplification via intracellular cascades mediated by heterotrimeric G-proteins. This high amplification system allows retinal rod photoreceptors to detect single photons of light. Although much is now known about the role of the α-subunit of the rod-specific G-protein transducin in phototransduction, the physiological function of the auxiliary βγ-complex in this process remains a mystery. Here, we show that elimination of the transducin γ-subunit drastically reduces signal amplification in intact mouse rods. The consequence is a striking decline in rod visual sensitivity and severe impairment of nocturnal vision. Our findings demonstrate that transducin βγ-complex controls signal amplification of the rod phototransduction cascade and is critical for the ability of rod photoreceptors to function in low light conditions.
- Published
- 2011
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13. Multiple pathways of inhibition shape bipolar cell responses in the retina.
- Author
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Eggers ED and Lukasiewicz PD
- Subjects
- Animals, Humans, Kinetics, Patch-Clamp Techniques, Receptors, GABA physiology, Receptors, GABA-A physiology, Receptors, Glycine physiology, Space Perception physiology, Retina physiology, Retinal Bipolar Cells physiology, Signal Transduction physiology
- Abstract
Bipolar cells (BCs) are critical relay neurons in the retina that are organized into parallel signaling pathways. The three main signaling pathways in the mammalian retina are the rod, ON cone, and OFF cone BCs. Rod BCs mediate incrementing dim light signals from rods, and ON cone and OFF cone BCs mediate incrementing and decrementing brighter light signals from cones, respectively. The outputs of BCs are shaped by inhibitory inputs from GABAergic and glycinergic amacrine cells in the inner plexiform layer, mediated by three distinct types of inhibitory receptors: GABA(A), GABA(C), and glycine receptors. The three main BC pathways receive distinct forms of inhibition from these three receptors that shape their light-evoked inhibitory signals. Rod BC inhibition is dominated by slow GABA(C) receptor inhibition, while OFF cone BCs are dominated by glycinergic inhibition. The inhibitory inputs to BCs are also shaped by serial inhibitory connections between GABAergic amacrine cells that limit the spatial profile of BC inhibition. We discuss our recent studies on how inhibitory inputs to BCs are shaped by receptor expression, receptor properties, and neurotransmitter release properties and how these affect the output of BCs.
- Published
- 2011
- Full Text
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14. Interneuron circuits tune inhibition in retinal bipolar cells.
- Author
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Eggers ED and Lukasiewicz PD
- Subjects
- Animals, Feedback, Physiological physiology, In Vitro Techniques, Inhibitory Postsynaptic Potentials, Interneurons physiology, Membrane Potentials physiology, Mice, Mice, Inbred C57BL, Neural Pathways physiology, Patch-Clamp Techniques, Photic Stimulation, Receptors, GABA metabolism, Receptors, GABA-A metabolism, Receptors, Glycine metabolism, Retinal Cone Photoreceptor Cells physiology, Retinal Rod Photoreceptor Cells physiology, Amacrine Cells physiology, Neural Inhibition physiology, Retinal Bipolar Cells physiology, Vision, Ocular physiology
- Abstract
While connections between inhibitory interneurons are common circuit elements, it has been difficult to define their signal processing roles because of the inability to activate these circuits using natural stimuli. We overcame this limitation by studying connections between inhibitory amacrine cells in the retina. These interneurons form spatially extensive inhibitory networks that shape signaling between bipolar cell relay neurons to ganglion cell output neurons. We investigated how amacrine cell networks modulate these retinal signals by selectively activating the networks with spatially defined light stimuli. The roles of amacrine cell networks were assessed by recording their inhibitory synaptic outputs in bipolar cells that suppress bipolar cell output to ganglion cells. When the amacrine cell network was activated by large light stimuli, the inhibitory connections between amacrine cells unexpectedly depressed bipolar cell inhibition. Bipolar cell inhibition elicited by smaller light stimuli or electrically activated feedback inhibition was not suppressed because these stimuli did not activate the connections between amacrine cells. Thus the activation of amacrine cell circuits with large light stimuli can shape the spatial sensitivity of the retina by limiting the spatial extent of bipolar cell inhibition. Because inner retinal inhibition contributes to ganglion cell surround inhibition, in part, by controlling input from bipolar cells, these connections may refine the spatial properties of the retinal output. This functional role of interneuron connections may be repeated throughout the CNS.
- Published
- 2010
- Full Text
- View/download PDF
15. Development of presynaptic inhibition onto retinal bipolar cell axon terminals is subclass-specific.
- Author
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Schubert T, Kerschensteiner D, Eggers ED, Misgeld T, Kerschensteiner M, Lichtman JW, Lukasiewicz PD, and Wong RO
- Subjects
- Age Factors, Animals, Animals, Newborn, Axons drug effects, Axons physiology, Bicuculline pharmacology, Drug Interactions physiology, GABA Antagonists pharmacology, Glycine Agents pharmacology, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, In Vitro Techniques, Inhibitory Postsynaptic Potentials physiology, Luminescent Proteins genetics, Luminescent Proteins metabolism, Mice, Mice, Transgenic, Patch-Clamp Techniques methods, Phosphinic Acids pharmacology, Potassium Channels, Inwardly Rectifying genetics, Potassium Channels, Inwardly Rectifying metabolism, Pyridazines pharmacology, Pyridines pharmacology, Receptors, Metabotropic Glutamate genetics, Retina growth & development, Retinal Bipolar Cells cytology, Strychnine pharmacology, Neural Inhibition physiology, Presynaptic Terminals physiology, Retina cytology, Retinal Bipolar Cells classification, Retinal Bipolar Cells physiology
- Abstract
Synaptic integration is modulated by inhibition onto the dendrites of postsynaptic cells. However, presynaptic inhibition at axonal terminals also plays a critical role in the regulation of neurotransmission. In contrast to the development of inhibitory synapses onto dendrites, GABAergic/glycinergic synaptogenesis onto axon terminals has not been widely studied. Because retinal bipolar cells receive subclass-specific patterns of GABAergic and glycinergic presynaptic inhibition, they are a good model for studying the development of inhibition at axon terminals. Here, using whole cell recording methods and transgenic mice in which subclasses of retinal bipolar cells are labeled, we determined the temporal sequence and patterning of functional GABAergic and glycinergic input onto the major subclasses of bipolar cells. We found that the maturation of GABAergic and glycinergic synapses onto the axons of rod bipolar cells (RBCs), on-cone bipolar cells (ON-CBCs) and off-cone bipolar cells (OFF-CBCs) were temporally distinct: spontaneous chloride-mediated currents are present in RBCs earlier in development compared with ON- and OFF-CBC, and RBCs receive GABAergic and glycinergic input simultaneously, whereas in OFF-CBCs, glycinergic transmission emerges before GABAergic transmission. Because on-CBCs show little inhibitory activity, GABAergic and glycinergic events could not be pharmacologically distinguished for these bipolar cells. The balance of GABAergic and glycinergic input that is unique to RBCs and OFF-CBCs is established shortly after the onset of synapse formation and precedes visual experience. Our data suggest that presynaptic modulation of glutamate transmission from bipolar cells matures rapidly and is differentially coordinated for GABAergic and glycinergic synapses onto distinct bipolar cell subclasses.
- Published
- 2008
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16. Nyctalopin expression in retinal bipolar cells restores visual function in a mouse model of complete X-linked congenital stationary night blindness.
- Author
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Gregg RG, Kamermans M, Klooster J, Lukasiewicz PD, Peachey NS, Vessey KA, and McCall MA
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Adaptation, Ocular physiology, Alcohol Oxidoreductases, Animals, Calbindins, Co-Repressor Proteins, DNA-Binding Proteins metabolism, Disease Models, Animal, Electroretinography methods, Excitatory Amino Acid Agonists pharmacology, Gene Expression genetics, Glutamic Acid pharmacology, Humans, Luminescent Proteins genetics, Luminescent Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Immunoelectron methods, Phosphoproteins metabolism, Proteoglycans genetics, Receptors, Metabotropic Glutamate metabolism, Retinal Bipolar Cells physiology, Retinal Bipolar Cells ultrastructure, S100 Calcium Binding Protein G metabolism, Night Blindness genetics, Night Blindness pathology, Proteoglycans metabolism, Retina physiology, Retinal Bipolar Cells metabolism, X Chromosome genetics
- Abstract
Mutations in the NYX gene that encodes the protein nyctalopin cause congenital stationary night blindness type 1. In no b-wave (nob) mice, a mutation in Nyx results in a functional phenotype that includes the absence of the electroretinogram b-wave and abnormal spontaneous and light-evoked activity in retinal ganglion cells (RGCs). In contrast, there is no morphological abnormality in the retina at either the light or electron microscopic levels. These functional deficits suggest that nyctalopin is required for normal synaptic transmission between retinal photoreceptors and depolarizing bipolar cells (DBCs). However, the synaptic etiology and, specifically, the exact location and function of nyctalopin, remain uncertain. We show that nob DBCs fail to respond to exogenous application of the photoreceptor neurotransmitter, glutamate, thus demonstrating a postsynaptic deficit in photoreceptor to bipolar cell communication. To determine if postsynaptic expression of nyctalopin is necessary and sufficient to rescue the nob phenotype, we constructed transgenic mice that expressed an EYFP-nyctalopin fusion protein on the dendritic tips of the DBCs. Immunohistochemical and ultrastructural studies verified that fusion protein expression was limited to the DBC dendritic tips. Fusion gene expression in nob mice restored normal outer and inner visual function as determined by the electroretinogram and RGC spontaneous and evoked responses. Together, our data show that nyctalopin expression on DBC dendrites is required for normal function of the murine retina.
- Published
- 2007
- Full Text
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17. Presynaptic inhibition differentially shapes transmission in distinct circuits in the mouse retina.
- Author
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Eggers ED, McCall MA, and Lukasiewicz PD
- Subjects
- Animals, Electrophysiology, In Vitro Techniques, Inhibitory Postsynaptic Potentials physiology, Light, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, GABA physiology, Receptors, GABA-A physiology, Receptors, Glycine physiology, Retinal Bipolar Cells classification, Retinal Bipolar Cells physiology, Retinal Bipolar Cells radiation effects, Retinal Cone Photoreceptor Cells physiology, Retinal Rod Photoreceptor Cells physiology, Neural Inhibition physiology, Presynaptic Terminals physiology, Retina physiology, Signal Transduction physiology, Synaptic Transmission physiology
- Abstract
Diverse retinal outputs are mediated by ganglion cells that receive excitatory input from distinct classes of bipolar cells (BCs). These classes of BCs separate visual signals into rod, ON and OFF cone pathways. Although BC signalling is a major determinant of the ganglion cell-mediated retinal output, it is not fully understood how light-evoked, presynaptic inhibition from amacrine cell inputs shapes BC outputs. To determine whether differences in presynaptic inhibition uniquely modulate BC synaptic output to specific ganglion cells, we assessed the inhibitory contributions of GABA(A), GABA(C) and glycine receptors across the BC pathways. Here we show that different proportions of GABA(A) and GABA(C) receptor-mediated inhibition determined the kinetics of GABAergic presynaptic inhibition across different BC classes. Large, slow GABA(C) and small, fast GABA(A) receptor-mediated inputs to rod BCs prolonged light-evoked inhibitory postsynaptic currents (L-IPSCs), while smaller GABA(C) and larger GABA(A) receptor-mediated contributions produced briefer L-IPSCs in ON and OFF cone BCs. Glycinergic inhibition also varied across BC class. In the rod-dominant conditions studied here, slow glycinergic inputs dominated L-IPSCs in OFF cone BCs, attributable to inputs from the rod pathway via AII amacrine cells, while rod and ON cone BCs received little and no glycinergic input, respectively. As these large glycinergic inputs come from rod signalling pathways, in cone-dominant conditions L-IPSCs in OFF cone bipolar cells will probably be dominated by GABA(A) receptor-mediated input. Thus, unique presynaptic receptor combinations mediate distinct forms of inhibition to selectively modulate BC outputs, enhancing the distinctions among parallel retinal signals.
- Published
- 2007
- Full Text
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18. Carbonic anhydrase XIV deficiency produces a functional defect in the retinal light response.
- Author
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Ogilvie JM, Ohlemiller KK, Shah GN, Ulmasov B, Becker TA, Waheed A, Hennig AK, Lukasiewicz PD, and Sly WS
- Subjects
- Animals, Carbonic Anhydrase IV deficiency, Electroretinography, Genotype, Mice, Mice, Knockout, Photic Stimulation, Retina cytology, Retina enzymology, Retinal Bipolar Cells cytology, Retinal Bipolar Cells enzymology, Retinal Bipolar Cells radiation effects, Carbonic Anhydrases deficiency, Light, Retina physiopathology, Retina radiation effects
- Abstract
Members of the carbonic anhydrase (CA) family play an important role in the regulation of pH, CO(2), ion, and water transport. CA IV and CA XIV are membrane-bound isozymes expressed in the eye. CA IV immunostaining is limited to the choriocapillaris overlying the retina, whereas CA XIV is expressed within the retina in Müller glial cells and retinal pigment epithelium. Here, we have characterized the physiological and morphological phenotype of the CA IV-null, CA XIV-null, and CA IV/CA XIV-double-null mouse retinas. Flash electroretinograms performed at 2, 7, and 10 months of age showed that the rod/cone a-wave, b-wave, and cone b-wave were significantly reduced (26-45%) in the CA XIV-null mice compared with wild-type littermates. Reductions in the dark-adapted response were not progressive between 2 and 10 months, and no differences in retinal morphology were observed between wild-type and CA XIV-null mice. Müller cells and rod bipolar cells had a normal appearance. Retinas of CA IV-null mice showed no functional or morphological differences compared with normal littermates. However, CA IV/CA XIV double mutants showed a greater deficit in light response than the CA XIV-null retina. Our results indicate that CA XIV, which regulates extracellular pH and pCO(2), plays an important part in producing a normal retinal light response. A larger functional deficit in the CA IV/CA XIV double mutants suggests that CA IV can also contribute to pH regulation, at least in the absence of CA XIV.
- Published
- 2007
- Full Text
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19. Ambient light regulates sodium channel activity to dynamically control retinal signaling.
- Author
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Ichinose T and Lukasiewicz PD
- Subjects
- Amacrine Cells cytology, Amacrine Cells metabolism, Animals, Cell Communication physiology, Dopamine metabolism, Dopamine Agonists pharmacology, Dopamine Antagonists pharmacology, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, Lighting, Organ Culture Techniques, Patch-Clamp Techniques, Photic Stimulation, Receptors, Dopamine D1 physiology, Retinal Bipolar Cells cytology, Adaptation, Ocular physiology, Light, Retinal Bipolar Cells physiology, Signal Transduction physiology, Sodium Channels physiology
- Abstract
The retinal network increases its sensitivity in low-light conditions to detect small visual inputs and decreases its sensitivity in bright-light conditions to prevent saturation. However, the cellular mechanisms that adjust visual signaling in the retinal network are not known. Here, we show that voltage-gated sodium channels in bipolar cells dynamically control retinal light sensitivity. In dim conditions, sodium channels amplified light-evoked synaptic responses mediated by cone pathways. Conversely, in bright conditions, sodium channels were inactivated by dopamine released from amacrine cells, and they did not amplify synaptic inputs, minimizing signal saturation. Our findings demonstrate that bipolar cell sodium channels mediate light adaptation by controlling retinal signaling gain.
- Published
- 2007
- Full Text
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20. Receptor and transmitter release properties set the time course of retinal inhibition.
- Author
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Eggers ED and Lukasiewicz PD
- Subjects
- Amacrine Cells drug effects, Amacrine Cells metabolism, Animals, Female, Glutamic Acid metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neural Inhibition drug effects, Neural Pathways cytology, Neural Pathways drug effects, Neurons cytology, Neurons drug effects, Neurotransmitter Agents pharmacology, Photic Stimulation, Reaction Time drug effects, Reaction Time physiology, Receptors, GABA drug effects, Receptors, GABA metabolism, Receptors, Glycine drug effects, Receptors, Glycine metabolism, Receptors, Neurotransmitter agonists, Receptors, Neurotransmitter antagonists & inhibitors, Retina cytology, Retina drug effects, Retinal Bipolar Cells drug effects, Retinal Bipolar Cells metabolism, Synaptic Membranes drug effects, Synaptic Membranes metabolism, Synaptic Transmission drug effects, Time Factors, Vision, Ocular drug effects, Vision, Ocular physiology, Neural Inhibition physiology, Neural Pathways metabolism, Neurons metabolism, Neurotransmitter Agents metabolism, Receptors, Neurotransmitter metabolism, Retina metabolism, Synaptic Transmission physiology
- Abstract
Synaptic inhibition is determined by the properties of postsynaptic receptors, neurotransmitter release, and clearance, but little is known about how these factors shape sensation-evoked inhibition. The retina is an ideal system to investigate inhibition because it can be activated physiologically with light, and separate inhibitory pathways can be assayed by recording from rod bipolar cells that possess distinct glycine, GABA(A), and GABA(C) receptors (R). We show that receptor properties differentially shape spontaneous IPSCs, whereas both transmitter release and receptor properties shape light-evoked (L) IPSCs. GABA(C)R-mediated IPSCs decayed the slowest, whereas glycineR- and GABA(A)R-mediated IPSCs decayed more rapidly. Slow GABA(C)Rs determined the L-IPSC decay, whereas GABA(A)Rs and glycineRs, which mediated rapid onset responses, determined the start of the L-IPSC. Both fast and slow inhibitory inputs distinctly shaped the output of rod bipolar cells. The slow GABA(C)Rs truncated glutamate release, making the A17 amacrine cell L-EPSCs more transient, whereas the fast GABA(A)R and glycineRs reduced the initial phase of glutamate release, limiting the peak amplitude of the L-EPSC. Estimates of transmitter release time courses suggested that glycine release was more prolonged than GABA release. The time course of GABA release activating GABA(C)Rs was slower than that activating GABA(A)Rs, consistent with spillover activation of GABA(C)Rs. Thus, both postsynaptic receptor and transmitter release properties shape light-evoked inhibition in retina.
- Published
- 2006
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21. Presynaptic inhibition modulates spillover, creating distinct dynamic response ranges of sensory output.
- Author
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Sagdullaev BT, McCall MA, and Lukasiewicz PD
- Subjects
- Action Potentials drug effects, Animals, GABA Antagonists pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Neural Inhibition drug effects, Neurons, Afferent drug effects, Organ Culture Techniques, Photic Stimulation methods, Presynaptic Terminals drug effects, Receptors, GABA physiology, Action Potentials physiology, Neural Inhibition physiology, Neurons, Afferent physiology, Presynaptic Terminals physiology
- Abstract
Sensory information is thought to be modulated by presynaptic inhibition. Although this form of inhibition is a well-studied phenomenon, it is still unclear what role it plays in shaping sensory signals in intact circuits. By visually stimulating the retinas of transgenic mice lacking GABAc receptor-mediated presynaptic inhibition, we found that this inhibition regulated the dynamic range of ganglion cell (GC) output to the brain. Presynaptic inhibition acted differentially upon two major retinal pathways; its elimination affected GC responses to increments, but not decrements, in light intensity across the visual scene. The GC dynamic response ranges were different because presynaptic inhibition limited glutamate release from ON, but not OFF, bipolar cells, which modulate the extent of glutamate spillover and activation of perisynaptic NMDA receptors at ON GCs. Our results establish a role for presynaptic inhibitory control of spillover in determining sensory output in the CNS.
- Published
- 2006
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22. GABA(A), GABA(C) and glycine receptor-mediated inhibition differentially affects light-evoked signalling from mouse retinal rod bipolar cells.
- Author
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Eggers ED and Lukasiewicz PD
- Subjects
- Animals, Cells, Cultured, Evoked Potentials, Visual radiation effects, GABA-A Receptor Antagonists, Light, Mice, Mice, Inbred C57BL, Radiation Dosage, Receptors, Glycine antagonists & inhibitors, Retinal Bipolar Cells radiation effects, Retinal Rod Photoreceptor Cells radiation effects, Synaptic Transmission physiology, Synaptic Transmission radiation effects, Evoked Potentials, Visual physiology, Neural Inhibition physiology, Receptors, GABA metabolism, Receptors, GABA-A metabolism, Receptors, Glycine metabolism, Retinal Bipolar Cells physiology, Retinal Rod Photoreceptor Cells physiology
- Abstract
Rod bipolar cells relay visual signals evoked by dim illumination from the outer to the inner retina. GABAergic and glycinergic amacrine cells contact rod bipolar cell terminals, where they modulate transmitter release and contribute to the receptive field properties of third order neurones. However, it is not known how these distinct inhibitory inputs affect rod bipolar cell output and subsequent retinal processing. To determine whether GABA(A), GABA(C) and glycine receptors made different contributions to light-evoked inhibition, we recorded light-evoked inhibitory postsynaptic currents (L-IPSCs) from rod bipolar cells mediated by each pharmacologically isolated receptor. All three receptors contributed to L-IPSCs, but their relative roles differed; GABA(C) receptors transferred significantly more charge than GABA(A) and glycine receptors. We determined how these distinct inhibitory inputs affected rod bipolar cell output by recording light-evoked excitatory postsynaptic currents (L-EPSCs) from postsynaptic AII and A17 amacrine cells. Consistent with their relative contributions to L-IPSCs, GABA(C) receptor activation most effectively reduced the L-EPSCs, while glycine and GABA(A) receptor activation reduced the L-EPSCs to a lesser extent. We also found that GABAergic L-IPSCs in rod bipolar cells were limited by GABA(A) receptor-mediated inhibition between amacrine cells. We show that GABA(A), GABA(C) and glycine receptors mediate functionally distinct inhibition to rod bipolar cells, which differentially modulated light-evoked rod bipolar cell output. Our findings suggest that modulating the relative proportions of these inhibitory inputs could change the characteristics of rod bipolar cell output.
- Published
- 2006
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23. Inner and outer retinal pathways both contribute to surround inhibition of salamander ganglion cells.
- Author
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Ichinose T and Lukasiewicz PD
- Subjects
- Animals, Bicuculline pharmacology, Carbenoxolone pharmacology, Cobalt pharmacology, Excitatory Postsynaptic Potentials drug effects, GABA Antagonists pharmacology, Organ Culture Techniques, Photic Stimulation, Picrotoxin pharmacology, Receptors, GABA physiology, Receptors, GABA-A physiology, Receptors, GABA-B physiology, Receptors, Presynaptic physiology, Urodela, Excitatory Postsynaptic Potentials physiology, Neural Inhibition physiology, Retinal Ganglion Cells physiology
- Abstract
Illumination of the receptive-field surround reduces the sensitivity of a retinal ganglion cell to centre illumination. The steady, antagonistic receptive-field surround of retinal ganglion cells is classically attributed to the signalling of horizontal cells in the outer plexiform layer (OPL). However, amacrine cell signalling in the inner plexiform layer (IPL) also contributes to the steady receptive-field surround of the ganglion cell. We examined the contributions of these two forms of presynaptic lateral inhibition to ganglion cell light sensitivity by measuring the effects of surround illumination on EPSCs evoked by centre illumination. GABA(C) receptor antagonists reduced inhibition attributed to dim surround illumination, suggesting that this inhibition was mediated by signalling to bipolar cell axon terminals. Brighter surround illumination further reduced the light sensitivity of the ganglion cell. The bright surround effects on the EPSCs were insensitive to GABA receptor blockers. Perturbing outer retinal signalling with either carbenoxolone or cobalt blocked the effects of the bright surround illumination, but not the effects of dim surround illumination. We found that the light sensitivities of presynaptic, inhibitory pathways in the IPL and OPL were different. GABA(C) receptor blockers reduced dim surround inhibition, suggesting it was mediated in the IPL. By contrast, carbenoxolone and cobalt reduced bright surround, suggesting it was mediated by horizontal cells in the OPL. Direct amacrine cell input to ganglion cells, mediated by GABA(A) receptors, comprised another surround pathway that was most effectively activated by bright illumination. Our results suggest that surround activation of lateral pathways in the IPL and OPL differently modulate the sensitivity of the ganglion cell to centre illumination.
- Published
- 2005
- Full Text
- View/download PDF
24. Sodium channels in transient retinal bipolar cells enhance visual responses in ganglion cells.
- Author
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Ichinose T, Shields CR, and Lukasiewicz PD
- Subjects
- Ambystoma growth & development, Animals, Choline pharmacology, Dendrites physiology, Interneurons ultrastructure, Ion Channel Gating, Larva, Lidocaine analogs & derivatives, Lidocaine pharmacology, Patch-Clamp Techniques, Photic Stimulation, Photoreceptor Cells, Vertebrate physiology, Retinal Ganglion Cells ultrastructure, Sodium metabolism, Sodium Channel Blockers pharmacology, Sodium Channels drug effects, Tetrodotoxin pharmacology, Time Factors, Interneurons physiology, Retinal Ganglion Cells physiology, Sodium Channels physiology, Visual Pathways physiology
- Abstract
Retinal bipolar cells are slow potential neurons that respond to photoreceptor inputs with graded potentials and do not fire action potentials. We found that transient ON bipolar cells recorded in retinal slices possess voltage-gated sodium channels located on either their dendrites or somas. The sodium currents in these neurons did not generate spikes but enhanced voltage responses evoked by visual stimulation, which selectively boosted transmission to transient ganglion cells. In contrast, sodium currents were not found in sustained ON bipolar cells, and light responses in sustained bipolar cells and ganglion cells were not affected by TTX. The presence of sodium channels in transient ON bipolar cells contributed to the separation of transient and sustained signals by selectively enhancing the responses of ON transient ganglion cells to light. Our results suggest that bipolar cell sodium channels augment transient signals and contribute to the temporal segregation of visual information.
- Published
- 2005
- Full Text
- View/download PDF
25. Synaptic mechanisms that shape visual signaling at the inner retina.
- Author
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Lukasiewicz PD
- Subjects
- Animals, Retina physiology, Signal Transduction physiology, Synapses physiology, Visual Pathways physiology
- Abstract
The retina is a layered structure that processes information in two stages. The outer plexiform layer (OPL) comprises the first stage and is where photoreceptors, bipolar cells, and horizontal cells interact synaptically. This is the synaptic layer where ON and OFF responses to light are formed, as well as the site where receptive field center and surround organization is first thought to occur. The inner plexiform layer (IPL) is where the second stage of synaptic interactions occurs. This synaptic layer is where subsequent visual processing occurs that may contribute to the formation of transient responses, which may underlie motion and direction sensitivity. In addition, synaptic interactions in the IPL may also contribute to the classical ganglion cell receptive field properties. This chapter will focus on the synapse and network properties at the IPL that sculpt light-evoked ganglion cell responses. These include synaptic mechanisms that may shape ganglion cell responses like desensitizing glutamate receptors and transporters, which remove glutamate from the synapse. Recent work suggests that inhibitory signaling at the IPL contributes to the surround receptive field organization of ganglion cells. A component of this amacrine cell inhibitory signaling is mediated by GABAC receptors, which are found on bipolar cell axon terminals in the IPL. Pharmacological experiments show that a component of the ganglion cell surround signal is mediated by these receptors, indicating that the ganglion cell center and surround receptive field organization is not formed entirely in the outer plexiform layer, as earlier thought.
- Published
- 2005
- Full Text
- View/download PDF
26. GABAC receptor-mediated inhibition in the retina.
- Author
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Lukasiewicz PD, Eggers ED, Sagdullaev BT, and McCall MA
- Subjects
- Animals, Electroretinography, Mice, Mice, Knockout, Receptors, GABA genetics, Receptors, GABA-A physiology, Retinal Ganglion Cells physiology, Vision, Ocular physiology, Neural Inhibition physiology, Receptors, GABA physiology, Retina physiology
- Abstract
Inhibition at bipolar cell axon terminals regulates excitatory signaling to ganglion cells and is mediated, in part, by GABAC receptors. We investigated GABAC receptor-mediated inhibition using pharmacological approaches and genetically altered mice that lack GABAC receptors. Responses to applied GABA showed distinct time courses in various bipolar cell classes, attributable to different proportions of GABAA and GABAC receptors. The elimination of GABAC receptors in GABAC null mice reduced and shortened GABA-activated currents and light-evoked inhibitory synaptic currents (L-IPSCs) in rod bipolar cells. ERG measurements and recordings from the optic nerve showed that inner retinal function was altered in GABAC null mice. These data suggest that GABAC receptors determine the time course and extent of inhibition at bipolar cell terminals that, in turn, modulates the magnitude of excitatory transmission from bipolar cells to ganglion cells.
- Published
- 2004
- Full Text
- View/download PDF
27. Spike-dependent GABA inputs to bipolar cell axon terminals contribute to lateral inhibition of retinal ganglion cells.
- Author
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Shields CR and Lukasiewicz PD
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Ambystoma, Anesthetics, Local pharmacology, Animals, Electrophysiology, Excitatory Amino Acid Agonists pharmacology, Excitatory Postsynaptic Potentials drug effects, Functional Laterality physiology, In Vitro Techniques, Ion Channel Gating drug effects, Ion Channel Gating physiology, Kainic Acid pharmacology, Neurons drug effects, Patch-Clamp Techniques, Photic Stimulation, Photoreceptor Cells drug effects, Presynaptic Terminals drug effects, Receptors, GABA drug effects, Retinal Ganglion Cells drug effects, Signal Transduction drug effects, Signal Transduction physiology, Sodium Channels drug effects, Sodium Channels physiology, Synaptic Transmission drug effects, Tetrodotoxin pharmacology, Neurons physiology, Presynaptic Terminals physiology, Receptors, GABA physiology, Retinal Ganglion Cells physiology
- Abstract
The inhibitory surround signal in retinal ganglion cells is usually attributed to lateral horizontal cell signaling in the outer plexiform layer (OPL). However, recent evidence suggests that lateral inhibition at the inner plexiform layer (IPL) also contributes to the ganglion cell receptive field surround. Although amacrine cell input to ganglion cells mediates a component of this lateral inhibition, it is not known if presynaptic inhibition to bipolar cell terminals also contributes to surround signaling. We investigated the role of presynaptic inhibition by recording from bipolar cells in the salamander retinal slice. TTX reduced light-evoked GABAergic inhibitory postsynaptic currents (IPSCs) in bipolar cells, indicating that presynaptic pathways mediate lateral inhibition in the IPL. Photoreceptor and bipolar cell synaptic transmission were unaffected by TTX, indicating that its main effect was in the IPL. To rule out indirect actions of TTX, we bypassed lateral signaling in the outer retina by either electrically stimulating bipolar cells or by puffing kainate (KA) directly onto amacrine cell processes lateral to the recorded cell. In bipolar and ganglion cells, TTX suppressed laterally evoked IPSCs, demonstrating that both pre- and postsynaptic lateral signaling in the IPL depended on action potentials. By contrast, locally evoked IPSCs in both cell types were only weakly suppressed by TTX, indicating that local inhibition was not as dependent on action potentials. Our results show a TTX-sensitive lateral inhibitory input to bipolar cell terminals, which acts in concert with direct lateral inhibition to give rise to the GABAergic surround in ganglion cells.
- Published
- 2003
- Full Text
- View/download PDF
28. Elimination of the rho1 subunit abolishes GABA(C) receptor expression and alters visual processing in the mouse retina.
- Author
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McCall MA, Lukasiewicz PD, Gregg RG, and Peachey NS
- Subjects
- Animals, Dark Adaptation physiology, Electroretinography drug effects, GABA Antagonists pharmacology, Gene Targeting, In Vitro Techniques, Mice, Mice, Inbred C57BL, Mice, Knockout, Neural Inhibition physiology, Neurons drug effects, Neurons physiology, Patch-Clamp Techniques, Photic Stimulation methods, Presynaptic Terminals drug effects, Presynaptic Terminals metabolism, Receptors, GABA genetics, Recombination, Genetic, Retina cytology, Retina drug effects, Retinal Rod Photoreceptor Cells physiology, Sequence Deletion genetics, Stem Cells, Stimulation, Chemical, Vision, Ocular genetics, gamma-Aminobutyric Acid pharmacology, Protein Subunits, Receptors, GABA deficiency, Receptors, GABA metabolism, Retina metabolism, Vision, Ocular physiology
- Abstract
Inhibition is crucial for normal function in the nervous system. In the CNS, inhibition is mediated primarily by the amino acid GABA via activation of two ionotropic GABA receptors, GABA(A) and GABA(C). GABA(A) receptor composition and function have been well characterized, whereas much less is known about native GABA(C) receptors. Differences in molecular composition, anatomical distributions, and physiological properties strongly suggest that GABA(A) receptors and GABA(C) receptors have distinct functional roles in the CNS. To determine the functional role of GABA(C) receptors, we eliminated their expression in mice using a knock-out strategy. Although native rodent GABA(C) receptors are composed of rho1 and rho2 subunits, we show that after rho1 subunit expression was selectively eliminated there was no GABA(C) receptor expression. We assessed GABA(C) receptor function in the retina because GABA(C) receptors are highly expressed on the axon terminals of rod bipolar cells and because this site modulates the visual signal to amacrine and ganglion cells. In GABA(C)rho1 null mice, GABA-evoked responses, normally mediated by GABA(C) receptors, were eliminated, and signaling from rod bipolar cells to third order cells was altered. These data demonstrate that elimination of the GABA(C)rho1 subunit, via gene targeting, results in the absence of GABA(C) receptors in the retina and selective alterations in normal visual processing.
- Published
- 2002
- Full Text
- View/download PDF
29. Activation of group II metabotropic glutamate receptors inhibits glutamate release from salamander retinal photoreceptors.
- Author
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Higgs MH and Lukasiewicz PD
- Subjects
- Ambystoma, Animals, Cyclopropanes pharmacology, Excitatory Postsynaptic Potentials drug effects, Glutamic Acid drug effects, Glycine pharmacology, In Vitro Techniques, Light, Receptors, Metabotropic Glutamate agonists, Retinal Cone Photoreceptor Cells physiology, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells physiology, Retinal Ganglion Cells radiation effects, Retinal Rod Photoreceptor Cells physiology, Glutamic Acid metabolism, Glycine analogs & derivatives, Photoreceptor Cells metabolism, Receptors, Metabotropic Glutamate physiology
- Abstract
We investigated the effects of group II metabotropic glutamate receptor (mGluR) activation on excitatory synaptic transmission in the salamander retinal slice preparation. The group II selective agonists DCG-IV and LY354740 reduced light-evoked excitatory postsynaptic currents (EPSCs) in ganglion cells. To determine the synaptic basis of this effect, we also recorded from bipolar cells and horizontal cells. In ON bipolar cells, DCG-IV increased the inward current in darkness but did not affect the peak current at light onset. In OFF bipolar cells and horizontal cells, DCG-IV had the opposite effect, reducing the inward current in darkness. Given the opposite polarities of these two classes of synapses, our results suggest that group II mGluRs act presynaptically to reduce glutamate release from photoreceptors. To determine whether DCG-IV affected rods or cones, we applied light stimuli that selectively activate each type of photoreceptor. In horizontal cells, most of which receive mixed synaptic input from rods and cones, DCG-IV reduced rod-driven EPSCs evoked by 470-nm stimuli and cone-driven EPSCs elicited by 700-nm stimuli in the presence of a rod-saturating background. Thus, activation of group II mGluRs reduced rod- and cone-mediated glutamate release. Our results suggest that group II mGluRs could mediate feedback by which extracellular glutamate inhibits glutamate release from photoreceptor terminals.
- Published
- 2002
- Full Text
- View/download PDF
30. GABA transporters regulate inhibition in the retina by limiting GABA(C) receptor activation.
- Author
-
Ichinose T and Lukasiewicz PD
- Subjects
- Animals, Carrier Proteins antagonists & inhibitors, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, GABA Antagonists pharmacology, GABA Plasma Membrane Transport Proteins, In Vitro Techniques, Kainic Acid pharmacology, Membrane Proteins antagonists & inhibitors, Neural Inhibition drug effects, Neurotransmitter Uptake Inhibitors pharmacology, Nipecotic Acids pharmacology, Oximes pharmacology, Patch-Clamp Techniques, Photic Stimulation, Receptors, GABA-A metabolism, Retina drug effects, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells metabolism, Stimulation, Chemical, Synaptic Transmission drug effects, Synaptic Transmission physiology, Urodela, Vision, Ocular physiology, gamma-Aminobutyric Acid pharmacology, Carrier Proteins metabolism, Membrane Proteins metabolism, Membrane Transport Proteins, Neural Inhibition physiology, Organic Anion Transporters, Receptors, GABA metabolism, Retina metabolism
- Abstract
Inhibition is mediated by two classes of ionotropic receptors in the retina, GABA(A) and GABA(C) receptors. We used the GABA transport blocker NO-711 to examine the role of GABA transporters in shaping synaptic responses mediated by these two receptors in the salamander retinal slice preparation. Focal applications (puffs) of GABA onto GABA(C) receptors on bipolar cells terminals or GABA(A) receptors on ganglion cells elicited currents that were enhanced by NO-711, demonstrating the presence of transporters in the inner plexiform layer (IPL). IPSCs were evoked in bipolar and ganglion cells by puffing kainate into the IPL. NO-711 enhanced the IPSCs only in bipolar cells, suggesting that, when GABA uptake was blocked, the GABA(C) receptors were more strongly activated by spillover transmission than the GABA(A) receptors on ganglion cells. NO-711 enhanced the light-evoked IPSCs mediated by GABA(C) receptors on bipolar cell axon terminals, which resulted in reduced transmission between bipolar and ganglion cells. NO-711 also shifted the intensity-response relationship of the ganglion cell, reducing its sensitivity to light. Surround illumination has been shown by others to produce similar shifts in ganglion cell light sensitivity. Our results show that GABA transporters limit the extent of inhibitory transmission at the inner retina during light-evoked signal processing.
- Published
- 2002
- Full Text
- View/download PDF
31. Morphological and electrophysiological evidence for an ionotropic GABA receptor of novel pharmacology.
- Author
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Shen DW, Higgs MH, Salvay D, Olney JW, Lukasiewicz PD, and Romano C
- Subjects
- Amacrine Cells drug effects, Amacrine Cells metabolism, Animals, Bicuculline pharmacology, Chick Embryo, Chickens, Excitatory Amino Acid Agonists pharmacology, GABA Antagonists pharmacology, In Vitro Techniques, Ion Transport drug effects, Kainic Acid pharmacology, Lithium pharmacology, Neurons drug effects, Nipecotic Acids pharmacology, Oximes pharmacology, Patch-Clamp Techniques, Picrotoxin pharmacology, Retina drug effects, Retina embryology, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells metabolism, Neurons metabolism, Receptors, GABA classification, Receptors, GABA metabolism, Retina metabolism
- Abstract
Evidence from toxicological studies suggested that an ionotropic GABA receptor of novel pharmacology (picrotoxin-insensitive, bicuculline-sensitive) exists in the chick embryo retina. In this report, we provide direct morphological and electrophysiological evidence for the existence of such an iGABA receptor. Chick embryo retinas (14-16 days old) incubated in the presence of kainic acid showed pronounced histopathology in all retinal layers. Maximal protection from this toxicity required a combination of bicuculline and picrotoxin. Individual application of the antagonists indicated that a picrotoxin-insensitive, bicuculline-sensitive GABA receptor is likely to be present on ganglion and amacrine, but not bipolar, cells. GABA currents in embryonic and mature chicken retinal neurons were measured by whole cell patch clamp. GABA was puffed at the dendritic processes in the IPL. Picrotoxin (500 microM, in the bath) eliminated all (>95%) the GABA current in the majority of ganglion and amacrine cells tested, but many cells possessed a substantial picrotoxin-insensitive component. This current was eliminated by bicuculline (200 microM). This current was not a transporter-associated current, since it was not altered by GABA transport blockers or sodium removal. The current-voltage relation was linear and reversed near E(Cl), as expected for a ligand-gated chloride current. Both pentobarbital and lorazepam enhanced the picrotoxin-insensitive current. We conclude that chicken retinal ganglion and amacrine cells express a GABA receptor that is GABA-A-like, in that it can be blocked by bicuculline, and positively modulated by barbiturates and benzodiazepines, but is insensitive to the noncompetitive blocker picrotoxin. Understanding the molecular properties of this receptor will be important for understanding both physiological GABA neurotransmission and the pathology of GABA receptor overactivation.
- Published
- 2002
- Full Text
- View/download PDF
32. Presynaptic effects of group III metabotropic glutamate receptors on excitatory synaptic transmission in the retina.
- Author
-
Higgs MH, Romano C, and Lukasiewicz PD
- Subjects
- Ambystoma, Animals, Animals, Newborn, Dose-Response Relationship, Drug, Electric Stimulation methods, Excitatory Amino Acid Agonists pharmacology, Excitatory Postsynaptic Potentials drug effects, Photic Stimulation methods, Receptors, Metabotropic Glutamate agonists, Receptors, Metabotropic Glutamate classification, Receptors, Presynaptic agonists, Retina drug effects, Synaptic Transmission drug effects, Excitatory Postsynaptic Potentials physiology, Receptors, Metabotropic Glutamate physiology, Receptors, Presynaptic physiology, Retina physiology, Synaptic Transmission physiology
- Abstract
Metabotropic glutamate receptors (mGluRs) are located in both plexiform layers in the retina and may modulate transmission between photoreceptors and bipolar cells and between bipolar and ganglion cells. We investigated whether mGluR activation modulates excitatory synaptic input to bipolar cells and ganglion cells in the salamander retinal slice preparation. The group III mGluR agonist L-2-amino-4-phosphonobutyric acid (AP4) inhibited monosynaptic excitatory postsynaptic currents (EPSCs) in ganglion cells evoked by electrical stimuli, whereas group I and group II agonists had no significant effect. AP4 reduced the frequency but not the amplitude of ganglion cell miniature EPSCs, suggesting a presynaptic action at bipolar cell terminals. AP4 also reduced ganglion cell EPSCs evoked by the offset of a light stimulus, suggesting that group III mGluRs modulate release from OFF bipolar cells. Comparison of light-evoked EPSCs in OFF bipolar cells and ganglion cells indicated that AP4 reduced ganglion cell EPSCs by acting primarily at bipolar cell terminals, and to a lesser extent at photoreceptor terminals. The group II/III mGluR antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) blocked the effect of AP4 at bipolar cell terminals, consistent with localization of group III mGluRs at these sites. However, CPPG did not increase EPSCs at light offset, indicating that activation of group III mGluRs by synaptic glutamate does not play a large role in modulating transmission from bipolar cells to ganglion cells.
- Published
- 2002
- Full Text
- View/download PDF
33. Mechanisms underlying developmental changes in the firing patterns of ON and OFF retinal ganglion cells during refinement of their central projections.
- Author
-
Myhr KL, Lukasiewicz PD, and Wong RO
- Subjects
- Action Potentials drug effects, Aging physiology, Animals, Dihydro-beta-Erythroidine pharmacology, Excitatory Amino Acid Antagonists pharmacology, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials physiology, Ferrets, GABA Antagonists pharmacology, Glycine Agents pharmacology, In Vitro Techniques, Patch-Clamp Techniques, Retina cytology, Retinal Ganglion Cells classification, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells physiology, Sensory Thresholds drug effects, Sensory Thresholds physiology, Signal Processing, Computer-Assisted, Action Potentials physiology, Retina growth & development, Retina physiology
- Abstract
Patterned neuronal activity is implicated in the refinement of connectivity during development. Calcium-imaging studies of the immature ferret visual system demonstrated previously that functionally separate ON and OFF retinal ganglion cells (RGCs) develop distinct temporal patterns of spontaneous activity as their axonal projections undergo refinement. OFF RGCs become spontaneously more active compared with ON cells, resulting in a decrease in synchronous activity between these cell types. This change in ON and OFF activity patterns is suitable for driving the activity-dependent refinement of their axonal projections. Here, we used whole-cell and perforated-patch recording techniques to elucidate the mechanisms that underlie the developmental alteration in the ON and OFF RGC activity patterns. First, we show that before the refinement period, ON and OFF RGCs have similar spike patterns; however, during the period of segregation, OFF RGCs demonstrate significantly higher spike rates relative to ON cells. With increasing age, OFF cells require less depolarization to reach their action potential threshold and fire more spikes in response to current injection compared with ON cells. In addition, spontaneous postsynaptic currents and potentials are greater in magnitude in OFF cells than ON cells. In contrast, before axonal refinement, there are no differences in the intrinsic excitability or synaptic drive onto ON and OFF cells. Together, our results show that developmental changes in ON and OFF RGC excitability and in the strength of their synaptic drives act together to reshape the spike patterns of these cells in a manner appropriate for the refinement of their connectivity.
- Published
- 2001
34. Distinct ionotropic GABA receptors mediate presynaptic and postsynaptic inhibition in retinal bipolar cells.
- Author
-
Shields CR, Tran MN, Wong RO, and Lukasiewicz PD
- Subjects
- Animals, Dendrites physiology, Evoked Potentials, Ferrets, Patch-Clamp Techniques, Receptors, GABA-A physiology, Retina cytology, Excitatory Postsynaptic Potentials physiology, Presynaptic Terminals physiology, Receptors, GABA physiology, Retina physiology
- Abstract
Ionotropic GABA receptors can mediate presynaptic and postsynaptic inhibition. We assessed the contributions of GABA(A) and GABA(C) receptors to inhibition at the dendrites and axon terminals of ferret retinal bipolar cells by recording currents evoked by focal application of GABA in the retinal slice. Currents elicited at the dendrites were mediated predominantly by GABA(A) receptors, whereas responses evoked at the terminals had GABA(A) and GABA(C) components. The ratio of GABA(C) to GABA(A) (GABA(C):GABA(A)) was highest in rod bipolar cell terminals and variable among cone bipolars, but generally was lower in OFF than in ON classes. Our results also suggest that the GABA(C):GABA(A) could influence the time course of responses. Currents evoked at the terminals decayed slowly in cell types for which the GABA(C):GABA(A) was high, but decayed relatively rapidly in cells for which this ratio was low. Immunohistochemical studies corroborated our physiological results. GABA(A) beta2/3 subunit immunoreactivity was intense in the outer and inner plexiform layers (OPL and IPL, respectively). GABA(C) rho subunit labeling was weak in the OPL but strong in the IPL in which puncta colocalized with terminals of rod bipolars immunoreactive for protein kinase C and of cone bipolars immunoreactive for calbindin or recoverin. These data demonstrate that GABA(A) receptors mediate GABAergic inhibition on bipolar cell dendrites in the OPL, that GABA(A) and GABA(C) receptors mediate inhibition on axon terminals in the IPL, and that the GABA(C):GABA(A) on the terminals may tune the response characteristics of the bipolar cell.
- Published
- 2000
35. GABA(C) receptors control adaptive changes in a glycinergic inhibitory pathway in salamander retina.
- Author
-
Cook PB, Lukasiewicz PD, and McReynolds JS
- Subjects
- Adaptation, Ocular physiology, Ambystoma, Animals, Darkness, Evoked Potentials drug effects, In Vitro Techniques, Kinetics, Larva, Patch-Clamp Techniques, Picrotoxin pharmacology, Reaction Time, Retinal Ganglion Cells drug effects, Glycine pharmacology, Receptors, GABA physiology, Retina physiology, Retinal Ganglion Cells physiology
- Abstract
We studied the role of GABA in adaptive changes in a lateral inhibitory system in the tiger salamander retina. In dark-adapted retinal slice preparations picrotoxin caused a slow enhancement of glycine-mediated IPSCs in ganglion cells. The enhancement of glycinergic IPSCs developed slowly over the course of 5-20 min, even though picrotoxin blocked both GABA(A) and GABA(C) receptors within a few seconds. The slow enhancement of glycinergic IPSCs by picrotoxin was much weaker in light-adapted preparations. The slow enhancement of glycinergic inhibitory inputs was not produced by bicuculline, indicating that it involved GABA(C) receptors. The responses of ganglion cells to direct application of glycine were not enhanced by picrotoxin, indicating that the enhancement was not caused by an action on glycine receptors. In dark-adapted eyecup preparations picrotoxin caused a slow enhancement of glycinergic IPSPs and transient lateral inhibition produced by a rotating windmill pattern, similar to the effect of light adaptation. The results suggest that the glycinergic inhibitory inputs are modulated by an unknown substance whose synthesis and/or release is inhibited in dark-adapted retinas by GABA acting at GABA(C) receptors.
- Published
- 2000
36. AMPA receptor kinetics limit retinal amacrine cell excitatory synaptic responses.
- Author
-
Tran MN, Higgs MH, and Lukasiewicz PD
- Subjects
- Animals, Benzodiazepines pharmacology, Benzothiadiazines pharmacology, Excitatory Amino Acid Antagonists pharmacology, Excitatory Postsynaptic Potentials drug effects, Glycine metabolism, In Vitro Techniques, Kinetics, Patch-Clamp Techniques, Receptors, AMPA antagonists & inhibitors, Retina cytology, Retina drug effects, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells metabolism, Urodela anatomy & histology, Excitatory Postsynaptic Potentials physiology, Receptors, AMPA metabolism, Retina physiology, Urodela physiology
- Abstract
Amacrine cells that respond transiently to maintained illumination are thought to mediate transient inhibitory input to ganglion cells. The excitation of these transient amacrine cells is thought to be limited by inhibitory feedback to bipolar cells. We investigated the possibility that desensitizing AMPA and/or kainate (KA) receptors on amacrine cells might also limit the duration of amacrine cell excitation. To determine how these receptors might affect amacrine cell input and output, we made whole-cell recordings from amacrine and ganglion cells in the salamander retinal slice. The specific AMPA receptor antagonist GYKI-53655 blocked non-NMDA receptor-mediated amacrine cell excitatory postsynaptic currents (EPSCs) and kainate puff-elicited currents, indicating that AMPA, and not KA, receptors mediated the responses. Cyclothiazide, an agent that reduces AMPA receptor desensitization, increased the amplitude and duration of amacrine cell EPSCs. To measure the output of transient amacrine cells, we recorded glycinergic inhibitory postsynaptic currents (IPSCs) from ganglion cells, and found that these were also enhanced by cyclothiazide. Thus, prolongation of amacrine cell AMPA receptor activation enhanced amacrine cell output. Current responses elicited by puffing glycine onto ganglion cell dendrites were not affected by cyclothiazide, indicating that the enhancement of glycinergic IPSCs was not due to a direct effect on glycine receptors. These data suggest that rapid AMPA receptor desensitization and/or deactivation limits glycinergic amacrine cell excitation and the resulting inhibitory synaptic output.
- Published
- 1999
- Full Text
- View/download PDF
37. Glutamate uptake limits synaptic excitation of retinal ganglion cells.
- Author
-
Higgs MH and Lukasiewicz PD
- Subjects
- Animals, Excitatory Postsynaptic Potentials, Quantum Theory, Urodela, Glutamic Acid metabolism, Retinal Ganglion Cells physiology, Synaptic Transmission physiology
- Abstract
EPSCs of retinal ganglion cells decay more slowly than do those of most other CNS neurons, in part because of the long time course of glutamate release from bipolar cells. Here we investigated how glutamate clearance and AMPA receptor desensitization affect ganglion cell EPSCs in the salamander retinal slice preparation. Inhibition of glutamate uptake greatly prolonged ganglion cell EPSCs evoked by light or monosynaptic electrical stimuli but had little effect on spontaneous miniature EPSCs (mEPSCs). This suggests that single quanta of glutamate are cleared rapidly by diffusion but multiple quanta can interact to lengthen the postsynaptic response. Some interaction between quanta is likely to occur even when glutamate uptake is not inhibited. This seems to depend on quantal content, because reducing glutamate release with low Ca2+, paired-pulse depression, or weak stimuli shortened the EPSC decay. High quantal content glutamate release may lead to desensitization of postsynaptic receptors. We reduced the extent of AMPA receptor desensitization by holding ganglion cells at positive potentials. This increased the amplitude of the late phase of evoked EPSCs but did not affect the decay rate after the first 50 msec of the response. In contrast, the holding potential had little effect on mEPSC kinetics. Our results suggest that desensitization limits the late phase of AMPA receptor-mediated EPSCs, whereas glutamate uptake controls the duration of both AMPA and NMDA receptor-mediated responses.
- Published
- 1999
38. Different combinations of GABAA and GABAC receptors confer distinct temporal properties to retinal synaptic responses.
- Author
-
Lukasiewicz PD and Shields CR
- Subjects
- Ambystoma, Animals, Electric Stimulation, Electrophysiology, Ion Channel Gating drug effects, Membrane Potentials drug effects, Membrane Potentials physiology, Microelectrodes, Patch-Clamp Techniques, Rats, Receptors, GABA-A drug effects, Retina cytology, Retina drug effects, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells physiology, Synapses drug effects, Time Factors, Receptors, GABA drug effects, Receptors, GABA physiology, Receptors, GABA-A physiology, Retina physiology, Synapses physiology
- Abstract
This study addresses how gamma-aminobutyric acid-A(GABAA) and GABAC receptors confer distinct temporal properties to neuronal synaptic responses. The retina is a model system for the study of postsynaptic contributions to synaptic responses because GABAergic amacrine cells synapse onto neurons, which have different combinations of GABAA and GABAC receptors. It is not known, however, how GABAA versus GABAC receptors influence the time course of retinal synaptic responses or what proportion of inhibitory input is mediated by each receptor type. We examined the time courses of synaptic responses mediated by GABA receptors in ganglion and bipolar cells by recording currents evoked by activating amacrine cells with a stimulating electrode in the salamander retinal slice. The pharmacologically isolated, GABAergic synaptic currents were long-lasting in bipolar cells and relatively brief in ganglion cells. The receptors that mediated these temporally distinct synaptic responses exhibited different pharmacological properties. In ganglion cells, GABAergic synaptic currents were abolished by the GABAA receptor antagonists bicuculline or SR95531. In bipolar cells, the GABAC receptor antagonist 3-aminopropyl[methyl]phosphonic acid (3-APMPA) largely blocked GABAergic synaptic responses; the remaining response was blocked by bicuculline or SR95531. The GABAA receptor component of the bipolar cell response was relatively brief compared with the GABAC receptor component. Puffing GABA onto ganglion cell dendrites or bipolar cell terminals yielded similar pharmacological and kinetic results, indicating that transmitter release differences did not determine the response time courses. Moreover, the GABAC receptors on bipolar cells may be different from those reported in rat or fish retina because imidazole-4-acetic acid (I4AA), which acts as an antagonist in these preparations, acts as an agonist in salamander. Our data show that the prolonged synaptic responses in bipolar cells were mediated predominantly by GABAC receptors, whereas transient synaptic responses in ganglion cells were mediated by GABAA receptors.
- Published
- 1998
- Full Text
- View/download PDF
39. A diversity of GABA receptors in the retina.
- Author
-
Lukasiewicz PD and Shields CR
- Subjects
- Animals, Receptors, GABA physiology, Retina physiology
- Abstract
GABA, a major inhibitory transmitter in the vertebrate retina, plays important roles in processing visual information. There are three functional families of retinal GABA receptors, the ionotropic GABAA and GABAC receptors and the metabotropic GABAB receptor. GABAC receptors are enriched in the retina, compared to other parts of the CNS. GABAC and GABAB receptors are found on subsets of neurons, whereas GABAA receptors are ubiquitous. The distinct functional properties of GABAA, GABAB and GABAC receptors suggests that individual neurons with different receptor complements have unique responses to GABA., (Copyright 1998 Academic Press.)
- Published
- 1998
- Full Text
- View/download PDF
40. Age-dependent and cell class-specific modulation of retinal ganglion cell bursting activity by GABA.
- Author
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Fischer KF, Lukasiewicz PD, and Wong RO
- Subjects
- Animals, Animals, Newborn, Bicuculline pharmacology, Electrophysiology, Female, Ferrets, GABA Antagonists pharmacology, GABA-A Receptor Agonists, GABA-A Receptor Antagonists, Glycine pharmacology, Glycine Agents pharmacology, Membrane Potentials drug effects, Membrane Potentials physiology, Periodicity, Picrotoxin pharmacology, Pregnancy, Pyridazines pharmacology, Retinal Ganglion Cells chemistry, Strychnine pharmacology, Aging physiology, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells physiology, gamma-Aminobutyric Acid pharmacology
- Abstract
Competition for postsynaptic targets during development is thought to be driven by differences in temporal patterns of neuronal activity. In the ferret visual system, retinal ganglion cells that are responsive either to the onset (On) or to the offset (Off) of light exhibit similar patterns of spontaneous bursting activity early in development but later develop different bursting rhythms during the period when their axonal arbors segregate to occupy spatially distinct regions in the dorsal lateral geniculate nucleus. Here, we demonstrate that GABAergic transmission plays an important, although not exclusive, role in regulating the bursting patterns of morphologically identified On and Off ganglion cells. During the first and second postnatal weeks, blocking GABAA receptors leads to a decrease in the bursting activity of all ganglion cells, suggesting that GABA potentiates activity at the early ages. Subsequently, during the period of On-Off segregation in the geniculate nucleus, GABA suppresses ganglion cell bursting activity. In particular, On ganglion cells show significantly higher bursting rates when GABAergic transmission is blocked, but the bursting rates of Off ganglion cells are not affected systematically. Thus, developmental differences in the bursting rates of On and Off ganglion cells emerge as GABA becomes inhibitory and as it consistently and more strongly inhibits On compared with Off ganglion cells. Because in many parts of the CNS GABAergic circuits appear early in development, our results also implicate a potentially important and possibly general role for local inhibitory interneurons in creating distinct temporal patterns of presynaptic activity that are specific to each developmental period.
- Published
- 1998
41. Action potentials are required for the lateral transmission of glycinergic transient inhibition in the amphibian retina.
- Author
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Cook PB, Lukasiewicz PD, and McReynolds JS
- Subjects
- Action Potentials physiology, Ambystoma growth & development, Animals, Glycine Agents pharmacology, In Vitro Techniques, Larva, Light, Necturus, Neural Inhibition drug effects, Retina drug effects, Retina radiation effects, Retinal Ganglion Cells drug effects, Retinal Ganglion Cells physiology, Retinal Ganglion Cells radiation effects, Strychnine pharmacology, Tetrodotoxin pharmacology, Time Factors, Amphibians physiology, Glycine physiology, Neural Inhibition physiology, Retina physiology, Synaptic Transmission physiology
- Abstract
Transient lateral inhibition (TLI), the suppression of responses of a ganglion cell to light stimuli in the receptive field center by changes in illumination in the receptive field surround, was studied in light-adapted mud puppy and tiger salamander retinas using both eyecup and retinal slice preparations. In the eyecup, TLI was measured in on-off ganglion cells as the ability of rotating, concentric windmill patterns of 500-1200 micron inner diameter to suppress the response to a small spot stimulus in the receptive field center. Both the suppression of the spot response and the hyperpolarization produced in ganglion cells by rotation of the windmill were blocked in the presence of 2 microM strychnine or 500 nM tetrodotoxin (TTX), but not by 150 microM picrotoxin. In the slice preparation in which GABA-mediated currents were blocked with picrotoxin, IPSCs elicited by diffuse illumination were blocked by strychnine and strongly reduced by TTX. The TTX-resistant component was probably attributable to illumination of the receptive field center. TTX had a much greater effect in reducing the glycinergic inhibition elicited by laterally displaced stimulation versus nearby focal electrical stimulation. Strychnine enhanced light-evoked excitatory currents in ganglion cells, but this was not mimicked by TTX. The results suggest that local glycinergic transient inhibition does not require action potentials and is mediated by synapses onto both ganglion cell dendrites and bipolar cell terminals. In contrast, the lateral spread of this inhibition (at least over distances >250 micron) requires action potentials and is mainly onto ganglion cell dendrites.
- Published
- 1998
42. Ca2+-independent excitotoxic neurodegeneration in isolated retina, an intact neural net: a role for Cl- and inhibitory transmitters.
- Author
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Chen Q, Olney JW, Lukasiewicz PD, Almli T, and Romano C
- Subjects
- Animals, Cell Survival drug effects, Chick Embryo, In Vitro Techniques, Receptors, N-Methyl-D-Aspartate physiology, Sodium physiology, Calcium physiology, Chlorides physiology, Excitatory Amino Acid Agonists toxicity, Kainic Acid toxicity, Neurotransmitter Agents physiology, Retina drug effects
- Abstract
Rapidly triggered excitotoxic cell death is widely thought to be due to excessive influx of extracellular Ca2+, primarily through the N-methyl-D-aspartate subtype of glutamate receptor. By devising conditions that permit the maintenance of isolated retina in the absence of Ca2+, it has become technically feasible to test the dependence of excitotoxic neurodegeneration in this intact neural system on extracellular Ca2+. Using biochemical, Ca2+ imaging, and electrophysiological techniques, we found that (1) rapidly triggered excitotoxic cell death in this system occurs independently of both extracellular Ca2+ and increases in intracellular Ca2+; (2) this cell death is highly dependent on extracellular Cl-; and (3) lethal Cl- entry occurs by multiple paths, but a significant fraction occurs through pathologically activated gamma-aminobutyric acid and glycine receptors. These results emphasize the importance of Ca2+-independent mechanisms and the role that local transmitter circuitry plays in excitotoxic cell death.
- Published
- 1998
- Full Text
- View/download PDF
43. Fenamates protect neurons against ischemic and excitotoxic injury in chick embryo retina.
- Author
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Chen Q, Olney JW, Lukasiewicz PD, Almli T, and Romano C
- Subjects
- Animals, Chick Embryo, Dizocilpine Maleate pharmacology, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Antagonists pharmacology, Flufenamic Acid pharmacology, Glucose pharmacology, Kainic Acid pharmacology, Meclofenamic Acid pharmacology, Mefenamic Acid pharmacology, N-Methylaspartate pharmacology, Organ Culture Techniques, Oxygen pharmacology, Patch-Clamp Techniques, Receptors, AMPA physiology, Receptors, Kainic Acid physiology, Receptors, N-Methyl-D-Aspartate physiology, Retinal Ganglion Cells chemistry, Retinal Ganglion Cells cytology, Retinal Ganglion Cells drug effects, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Brain Ischemia drug therapy, Neuroprotective Agents pharmacology, Neurotoxins pharmacology, ortho-Aminobenzoates pharmacology
- Abstract
Three fenamates (flufenamate, meclofenamate and mefenamate) were examined for their protective effect on neurons under ischemic (glucose/oxygen deprivation) or excitotoxic conditions, using the isolated retina of chick embryo as a model. Retinal damage was evaluated by histology and lactate dehydrogenase assay. Whole-cell recording was used to examine the direct effect of the fenamates on glutamate receptor-mediated currents. The fenamates protected the retina against the ischemic or excitotoxic insult. Part of the neuroprotection by the fenamates derived from inhibition of N-methyl-D-aspartate receptor-mediated currents. However, kainate receptor-mediated currents were not blocked by the fenamates, which nonetheless reduced kainate receptor-mediated retinal damage. Our results raise the possibility that fenamates may serve as lead structures in the development of novel therapeutic agents against brain ischemia.
- Published
- 1998
- Full Text
- View/download PDF
44. GABAC receptors on ferret retinal bipolar cells: a diversity of subtypes in mammals?
- Author
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Lukasiewicz PD and Wong RO
- Subjects
- Animals, Bicuculline pharmacology, GABA Antagonists pharmacology, Patch-Clamp Techniques, Picrotoxin pharmacology, Retina cytology, Species Specificity, Ferrets metabolism, Mammals metabolism, Rats metabolism, Receptors, GABA analysis, Retina chemistry
- Abstract
The GABAC receptor subtypes on bipolar cells of rats and cold-blooded vertebrates differ in their pharmacological properties and probably have different molecular compositions. With the exception of the rat, native GABAC receptors in mammals had not been studied. In ferret, whole-cell, voltage-clamp recordings were made from bipolar cells in the retinal slice preparation to determine which subtype of GABAC receptor predominated. Puff-evoked GABA currents in bipolar cells were partially reduced by the GABAA receptor antagonist bicuculline, indicating that both GABAA and GABAC receptors mediated the responses. By contrast, GABA currents of ganglion cells were always completely blocked by bicuculline, indicating that GABAA receptors predominated on these cells. Small-amplitude GABA currents of bipolar cells evoked by short-duration puffs were less sensitive to bicuculline than large-amplitude currents evoked by long-duration puffs. This indicates that GABAC receptors mediated proportionately more of the small-amplitude, puff-evoked responses and GABAA receptors mediated more of the large-amplitude, puff-evoked responses. In bipolar cells, the bicuculline-resistant component of the GABA current was entirely blocked by 3-APMPA (3-aminopropyl-(methyl)phosphonic acid), a GABAC receptor antagonist. Picrotoxin, which is relatively ineffective at rat GABAC receptors, completely blocked GABA currents in ferret bipolar cells, indicating that GABAC receptors on ferret bipolar cells resemble those in lower vertebrates rather than those in the rat retina. These results suggest that there may be a diversity of GABAC receptor subtypes on mammalian bipolar cells.
- Published
- 1997
- Full Text
- View/download PDF
45. AMPA-preferring receptors mediate excitatory synaptic inputs to retinal ganglion cells.
- Author
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Lukasiewicz PD, Wilson JA, and Lawrence JE
- Subjects
- Ambystoma, Animals, Benzodiazepines pharmacology, Dendrites drug effects, Electrophysiology, Evoked Potentials, Visual drug effects, Evoked Potentials, Visual physiology, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Antagonists pharmacology, Membrane Potentials drug effects, Membrane Potentials physiology, Microelectrodes, Patch-Clamp Techniques, Photic Stimulation, Potassium pharmacology, Receptors, AMPA antagonists & inhibitors, Receptors, AMPA drug effects, Receptors, Neurotransmitter drug effects, Retinal Ganglion Cells drug effects, Stimulation, Chemical, Anti-Anxiety Agents, Receptors, AMPA physiology, Receptors, Neurotransmitter physiology, Retinal Ganglion Cells physiology
- Abstract
Pharmacological studies were performed to determine whether alpha-amino-3-hydroxy-5-methyl-4-isoazoleprionic acid (AMPA)- and/or kainate (KA)-preferring receptors mediate excitatory synaptic inputs to tiger salamander retinal ganglion cells. Excitatory postsynaptic currents (EPSCs), evoked either by light or by stimulating bipolar cells with puffs of K+, were measured using whole cell recording techniques in the tiger salamander retinal slice. The AMPA/KA component of the EPSCs was isolated by including antagonists of glycine-, gamma-aminobutyric acid (GABA)- and NMDA-receptors in the bath. The AMPA-preferring receptor antagonists, 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI-52466) and 1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-7,8-methylenedioxy-3,4 - dihydro-5H-2,3-benzodiazepine (GYKI-53665), reduced light-evoked EPSCs and K+ puff-evoked EPSCs amplitudes in a concentration-dependent manner. The IC50 values for GYKI-52466 were 3.6 and 4.2 microM for the light- and puff-evoked responses, respectively. The more potent GYKI-53665 had IC50 values of 0.7 microM for both the light- and puff evoked responses. KA activates both KA- and AMPA-preferring receptors. KA-evoked currents were completely blocked by 10-40 microM GYKI-53665, indicating that little or no excitatory synaptic current was mediated by KA-preferring receptors. Concanavalin A, a compound that preferentially potentiates responses mediated by KA-preferring receptors, did not enhance either EPSCs or glutamate-evoked responses. By contrast, cyclothiazide, which selectively enhances AMPA-preferring receptor mediated responses, was found to enhance both EPSCs and glutamate-evoked currents. Our results indicate that the non-NMDA component of ganglion cell EPSCs is mediated by AMPA-preferring receptors and not significantly by KA-preferring receptors.
- Published
- 1997
- Full Text
- View/download PDF
46. GABAC receptors in the vertebrate retina.
- Author
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Lukasiewicz PD
- Subjects
- Animals, Invertebrates, Macromolecular Substances, Models, Structural, Protein Structure, Secondary, Receptors, GABA biosynthesis, Receptors, GABA-A physiology, Retina cytology, Vertebrates, Receptors, GABA chemistry, Receptors, GABA physiology, Retina physiology
- Abstract
In the central nervous system (CNS), the inhibitory transmitter GABA interacts with three subtypes of GABA receptors, type A, type B, and type C. Historically, GABA receptors have been classified as either the inotropic GABAA receptors or the metabotropic GABAB receptors. Over the past 10 yr, studies have shown that a third class, called the GABAC receptor, also exists. GABAC receptors are found primarily in the vertebrate retina and to some extent in other parts of the CNS. Although GABAA and GABAC receptors both gate chloride channels, they are pharmacologically, molecularly, and functionally distinct. The rho subunit of the GABAC receptor, which has about 35% amino acid homology to GABAA receptor subunits, was cloned from the retina and, when expressed in Xenopus oocytes, has properties similar to retinal GABAC receptors. There are probably distinct roles for GABAC receptors in the retina, because they are found on only a subset of neurons, whereas GABAA receptors are ubiquitous. This article reviews recent electrophysiological and molecular studies that have characterized the unique properties of GABAC receptors and describes the roles that these receptors may play in visual information processing in the retina.
- Published
- 1996
- Full Text
- View/download PDF
47. Immunocytochemical localization of polyamines in the tiger salamander retina.
- Author
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Valentino TL, Lukasiewicz PD, and Romano C
- Subjects
- Animals, Antibodies immunology, Ganglia metabolism, Immunohistochemistry, Urodela, Polyamines immunology, Polyamines metabolism, Retina metabolism, gamma-Aminobutyric Acid immunology
- Abstract
The polyamines spermine and spermidine are present in neural tissue, but their functions there are not well understood. Recent work suggests that the NMDA subtype of glutamate receptors, other glutamate receptor subtypes, and certain K(+)-channels, are neural targets for polyamines. To better understand the neuron-specific roles of polyamines, we have developed antibodies that interact with spermine and spermidine in aldehyde-fixed tissue and used these antibodies in immunocytochemical studies to determine the cellular localization of these polyamines in the tiger salamander retina. The affinity-purified, polyclonal antibodies were highly specific for spermine and spermidine, exhibiting < 1% cross reactivity with putrescine, and virtually no cross-reactivity with GABA, arginine, lysine, or glutaraldehyde. Polyamine labeling was most abundant in cells in the inner half of the inner nuclear layer and in the ganglion cell layer. Some cells in the outer half of the inner nuclear layer are labeled, and there was some labeling in both synaptic layers. Double-labeling experiments indicated (1) all GABAergic amacrine cells were polyamine-positive; and (2) all ganglion cells (identified by back-filling after microinjections of rhodamine in the optic nerve) were polyamine-positive. These results are consistent with a role for polyamines as modulators of NMDA receptor function and channel function in the inner retina.
- Published
- 1996
- Full Text
- View/download PDF
48. Synaptic transmission at N-methyl-D-aspartate receptors in the proximal retina of the mudpuppy.
- Author
-
Lukasiewicz PD and McReynolds JS
- Subjects
- 2-Amino-5-phosphonovalerate, Action Potentials drug effects, Amino Acids pharmacology, Animals, Aspartic Acid analogs & derivatives, Aspartic Acid pharmacology, In Vitro Techniques, N-Methylaspartate, Necturus, Receptors, Amino Acid, Retinal Ganglion Cells drug effects, Valine analogs & derivatives, Valine pharmacology, Receptors, Cell Surface physiology, Retina physiology, Synapses physiology, Synaptic Transmission drug effects
- Abstract
The effects of excitatory amino acid analogues and antagonists on retinal ganglion cells were studied using intracellular recording in the superfused mudpuppy eyecup preparation. Aspartate, glutamate, quisqualate (QA), kainate (KA) and N-methylaspartate (NMA) caused depolarization and decreased input resistance in all classes of ganglion cells. The order of sensitivity was QA greater than or equal to KA greater than NMA greater than aspartate greater than or equal to glutamate. All of these agonists were effective when transmitter release was blocked with 4 mM-Co2+ or Mn2+, indicating that they acted at receptor sites on the ganglion cells. At a concentration of 250 microM, 2-amino-5-phosphonovalerate (APV) blocked the responses of all ganglion cells to NMA, but not to QA or KA, indicating that NMA acts at different receptor sites from QA or KA. Responses to bath-applied aspartate and glutamate were reduced slightly or not at all in the presence of APV, indicating that they were acting mainly at non-NMDA (N-methyl-D-aspartate) receptors. In all ganglion cells 250 microM-APV strongly suppressed the sustained responses driven by the 'on'-pathway but not those driven by the 'off'-pathway. In most on-off ganglion cells the transient excitatory responses at 'light on' and 'light off' were not reduced by 500 microM-APV. APV-resistant transient excitatory responses were also present in some on-centre ganglion cells. APV did not block the transient inhibitory responses in any class of ganglion cells. At concentrations which blocked the sustained responses of ganglion cells, APV did not affect the sustained responses of bipolar cells, indicating that it acted at sites which were post-synaptic to bipolar cells. The simplest interpretation of these results is that the transmitter released by depolarizing bipolar cells acts at NMDA receptors on sustained depolarizing amacrine and ganglion cells. It may act at non-NMDA receptors at synapses which produce transient excitatory responses, but this could not be proved. The transmitter released by hyperpolarizing bipolar cells does not appear to act at NMDA receptors on any post-synaptic cells.
- Published
- 1985
- Full Text
- View/download PDF
49. Excitatory amino acids have different effects on horizontal cells in eyecup and isolated retina.
- Author
-
Miyachi E, Lukasiewicz PD, and McReynolds JS
- Subjects
- Amino Acids physiology, Animals, Diffusion, Electrophysiology, Evoked Potentials, Visual drug effects, In Vitro Techniques, Necturus, Photoreceptor Cells drug effects, Photoreceptor Cells physiology, Retina cytology, Retina physiology, Amino Acids pharmacology, Retina drug effects
- Abstract
Horizontal cells in the mudpuppy eyecup responded to continuous superfusion with L-glutamate, L-aspartate, kainate and quisqualate with a transient depolarization and reduction of the light evoked responses. However, in isolated retina preparations, in which these substances were applied to the photoreceptor side of the retina, the effects were sustained as long as the agonists were present. These results suggest that the transient action of these agonists in eyecup preparations was due to the rapid development of an intraretinal diffusion barrier, and are consistent with the hypothesis that photoreceptors release an excitatory amino acid transmitter.
- Published
- 1987
- Full Text
- View/download PDF
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