2-Amino-4-Phosphonobutyric Acid: A New Pharmacological Tool for Retina Research

Slaughter, Malcolm M.; Miller, Robert F.

doi:10.1126/science.6255566

Cited by 780 publications

(486 citation statements)

References 19 publications

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“…Pharmacological agents, L-2-amino-4-phosphonobutyric acid (APB) (1.6 -2.0 mM) to eliminate on bipolar cell light responses (Slaughter and Miller, 1981), cis-2,3-piperidinedicarboxylic acid (PDA) (5.2 -6.2 mM) to block Off bipolar and inner retinal light responses (Slaughter and Miller, 1983;Massey, 1990 for review), and a mixed solution of APB +PDA (same concentrations as reported for each) were injected into the eye (1.0 -1.5 μl) using a Hamilton microsyringe. (Hamilton Company, Reno, NV).…”

Section: Intravitreal Injectionmentioning

confidence: 99%

Postreceptoral contributions to the light-adapted ERG of mice lacking b-waves

Shirato

Maeda

Miura

et al. 2008

Experimental Eye Research

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The purpose of this study was to determine the contributions of postreceptoral neurons to the lightadapted ERG of the Nob mouse, a model for complete-type congenital stationary night blindness (CSNB1) that lacks a b-wave from depolarizing bipolar cells. Ganzfeld ERGs were recorded from anesthetized adult control mice, control mice injected intravitreally with L-2-amino-4-phosphonobutyric acid (Control APB mice) to remove On pathway activity, and Nob mice. ERGs also were recorded after PDA (cis-2, 3-piperidine-dicarboxylic acid, 3-5 mM) was injected to block transmission to hyperpolarizing (Off) bipolar and horizontal cells, and all 3rd order neurons. Stimuli were brief (< 4 ms, 0.4 -2.5 log sc td s) and long (200 ms, 2.5 -4.6 log sc td) LED flashes (λmax = 513 nm, on a rod suppressing background (2.6 log sc td). Sinusoidal modulation of the LEDs (mean, 2.6 log sc td; contrast, 100%; 3 to 36 Hz) was used to study flicker ERGs.Brief-flash ERGs of Nob mice presented as long-lasting negative waves with a positive-going intrusion that started about 50 ms after the flash and peaked around 120 ms. Control APB mice had similar responses, and in both cases, PDA removed the positive-going intrusion. For long flashes, PDA removed a small, slow "d-wave" after light offset. With sinusoidal stimulation, the fundamental (F1) amplitude of control mice ERG peaked at 8 Hz (~70 μV). For Nob mice the peak was ~20 μV at 6 Hz before PDA and ~10 μV at 3 Hz or lower after PDA. F1 responses were present up to 21 Hz in control and Nob eyes and 15 Hz in Nob eyes after PDA. Between 3 and 6 Hz, F1 phase was 170°-210° more delayed in Nob than control mice; phase was hardly altered by PDA. With vector analysis, a substantial postreceptoral input to the Nob flicker ERG was revealed. In control mice, the second harmonic (F2) response showed peaks of ~10 μV at 3 Hz and 13 Hz. Nob mice showed almost no F2. In summary, in this study it was found that in Nob mice, postreceptoral neurons from the Off pathway make a positive-going contribution to the light-adapted flash ERG, and contribute substantially to sinusoidal flicker ERG.

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Section: Intravitreal Injectionmentioning

confidence: 99%

Postreceptoral contributions to the light-adapted ERG of mice lacking b-waves

Shirato

Maeda

Miura

et al. 2008

Experimental Eye Research

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“…In the mature retina, this glutamate agonist hyperpolarizes On bipolar cells and rod bipolar cells, thereby preventing their release of glutamate (Slaughter and Miller, 1981;Bolz et al, 1984;Müller et al, 1988). However, nothing is known about the effects of APB on the visual responses of developing retinal ganglion cells.…”

Section: Effects Of Apb Application On the Visual Responses Of Develomentioning

confidence: 99%

“…What underlies the gradual retraction of initially multistratified ganglion cell dendrites remains to be established. It has been shown, however, that treating the postnatal cat retina with the glutamate analog 2-amino-4-phosphonobutric acid (APB), which in the mature retina hyperpolarizes On-cone bipolar cells and rod bipolar cells thereby preventing their release of glutamate (Slaughter and Miller, 1981;Bolz et al, 1984;Müller et al, 1988), results in a much higher than normal incidence of ganglion cells with multistratified dendrites (Bodnarenko and Chalupa, 1993;Bodnarenko et al, 1995). Interestingly, it is not activity per se that shapes this developmental process because the formation of stratified ganglion cells is not perturbed by intraocular TTX injections (Dubin et al, 1986;Wong et al, 1991) or by visual deprivation (Leventhal and Hirsch, 1983;Lau et al, 1990).…”

mentioning

confidence: 99%

Unique Functional Properties of On and Off Pathways in the Developing Mammalian Retina

2001

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In the mature retina, the dendrites of On and Off ganglion cells are segregated into separate sublaminas of the inner plexiform layer, but early in development these processes are multistratified, ramifying more widely within this synaptic layer. The dendritic pattern exhibited by immature ganglion cells suggests that there may be a functional convergence of On and Off pathways in the developing retina, but previous studies have provided evidence against this. Here we demonstrate by patchclamp recordings and dye filling that ganglion cells with multistratified dendrites respond to the onset, as well as the offset, of light. We further show that, in the dark-adapted retina, the glutamate analog 2-amino-4-phosphonobutric acid abolishes On and Off discharges in ganglion cells with multistratified dendrites. In contrast, in cells with stratified dendrites, this drug selectively blocks On responses. These findings provide evidence for unique functional attributes of On and Off pathways in the developing retina. The properties of immature ganglion cells documented here have important implications for the roles ascribed to neuronal activity in refining connections during the early development of the visual system.

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“…To test for a high tonic level of glutamate release, we measured the response in the membrane potential of an ON cell at several points after tonically hyperpolarizing the ON bipolar cell with the agonist of its metabotropic glutamate receptor (mGluR6), L-AP-4 (25-50 m; Shiells et al, 1981;Slaughter and Miller, 1981). L-AP-4 hyperpolarized the membrane potential and reduced the variance of the membrane potential (Fig.…”

Section: Polarizing the Cell Altered Rectification Of Spiking Responsesmentioning

confidence: 99%

“…The balance between ON and OFF cells can be disturbed by injecting L-AP-4 into the eye to hyperpolarize ON bipolar cells and therefore to block the output of ON ganglion cells (Shiells et al, 1981;Slaughter and Miller, 1981;Schiller, 1982). ON pathway blockade alters the receptive field properties of cortical cells and reduces psychophysical sensitivity to contrast, especially for a stimulus brighter than the background (Schiller, 1982;Sherk and Horton, 1984;Schiller et al, 1986;Dolan and Schiller, 1994).…”

Section: Introductionmentioning

confidence: 99%

Different Circuits for ON and OFF Retinal Ganglion Cells Cause Different Contrast Sensitivities

Zaghloul¹,

Boahen

Demb³

2003

J. Neurosci.

214

309

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The theory of "parallel pathways" predicts that, except for a sign reversal, ON and OFF ganglion cells are driven by a similar presynaptic circuit. To test this hypothesis, we measured synaptic inputs to ON and OFF cells as reflected in the subthreshold membrane potential. We made intracellular recordings from brisk-transient (Y) cells in the in vitro guinea pig retina and show that ON and OFF cells in fact express significant asymmetries in their synaptic inputs. An ON cell receives relatively linear input that modulates a single excitatory conductance; whereas an OFF cell receives rectified input that modulates both inhibitory and excitatory conductances. The ON pathway, blocked by L-AP-4, tonically inhibits an OFF cell at mean luminance and phasically inhibits an OFF cell during a light increment. Our results suggest that basal glutamate release is high at ON but not OFF bipolar terminals, and inhibition between pathways is unidirectional: ON 3 OFF. These circuit asymmetries explain asymmetric contrast sensitivity observed in spiking behavior.

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2-Amino-4-Phosphonobutyric Acid: A New Pharmacological Tool for Retina Research

Cited by 780 publications

References 19 publications

Postreceptoral contributions to the light-adapted ERG of mice lacking b-waves

Postreceptoral contributions to the light-adapted ERG of mice lacking b-waves

Unique Functional Properties of On and Off Pathways in the Developing Mammalian Retina

Different Circuits for ON and OFF Retinal Ganglion Cells Cause Different Contrast Sensitivities

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