ORCID Profile
0000-0002-6806-3249
Current Organisations
John Curtin School of Medical Research
,
University of California, Berkeley
,
University of New South Wales
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Publisher: Elsevier BV
Date: 03-2010
Publisher: Wiley
Date: 05-12-2012
Publisher: Wiley
Date: 31-08-2010
Publisher: Wiley
Date: 17-10-2011
DOI: 10.1002/CNE.22756
Publisher: Wiley
Date: 15-02-2010
DOI: 10.1002/CNE.22234
Publisher: Springer New York
Date: 28-12-2009
DOI: 10.1007/978-1-4419-1399-9_60
Abstract: Retinitis Pigmentosa (RP) refers to a heterogeneous group of inherited disorders that result in the death of rod and cone photoreceptors. There is now abundant evidence to suggest that inner retinal neurons, particularly the bipolar and horizontal cells, undergo significant morphological changes and changes in neurotransmitter receptor expression in response to photoreceptor degeneration. Some of these alterations could impact the choice and success of intervention strategies for these conditions, and it is therefore necessary to understand the timing and nature of any functional deficits resulting from degenerative changes. This paper will review the evidence for functional alterations in the inner retina in animal models of (RP), with particular emphasis on the bipolar and ganglion cells.
Publisher: Wiley
Date: 10-1991
DOI: 10.1113/JPHYSIOL.1991.SP018818
Abstract: 1. Photosensitivities of visual pigments were determined by measuring early receptor currents (ERCs) in voltage-cl ed photoreceptors from larval salamanders. 2. As expected from previous work of others, the ERC elicited by a brief flash consisted of a rapid inward component followed by a larger and slower outward component. The magnitude of the outward component corresponded to the movement of about 0.18 electronic charge across the membrane per photoisomerization. 3. The time course of the ERC was independent of the flash intensity, the flash wavelength and the magnitude of the response. The outward component of the cone ERC declined about twice as rapidly as the outward component of the rod ERC.. 4. The litude of the ERC decreased as successive flashes bleached the cell's pigment. Using the proportional relation between the size of the ERC and the number of pigment molecules photoisomerized, photosensitivities of the native A2 pigments in rods, red-sensitive cones, blue-sensitive cones and UV-sensitive cones were determined. Calculated solution photosensitivities for rhodopsin, red-sensitive and blue-sensitive cone pigments were not significantly different and the average value for all three pigments at their respective absorption maxima was (7.3 +/- 1.6) x 10(-9) micron 2 molecule-1. A value of 44.0 x 10(-9) micron 2 molecule-1 was obtained in a single UV-sensitive cone. 5. Substitution of the native dehydroretinal chromophore in the red-sensitive cone pigment with 11-cis-retinal increased the solution photosensitivity to (9.6 +/- 0.62) x 10(-9) micron 2 molecule-1. 6. We conclude that cone pigments have large molecular absorption cross-sections and high quantum efficiencies of photoisomerization. These properties seem well suited for the receptive molecules of a highly sensitive, miniaturized transducer.
Publisher: Wiley
Date: 15-01-2018
DOI: 10.1113/JP275195
Publisher: Wiley
Date: 04-2009
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.NEURON.2005.06.036
Abstract: Dendritic spikes that propagate toward the soma are well documented, but their physiological role remains uncertain. Our in vitro patch-cl recordings and two-photon calcium imaging show that direction-selective retinal ganglion cells (DSGCs) utilize orthograde dendritic spikes during physiological activity. DSGCs signal the direction of image motion. Excitatory subthreshold postsynaptic potentials are observed in DSGCs for motion in all directions and provide a weakly tuned directional signal. However, spikes are generated over only a narrow range of motion angles, indicating that spike generation greatly enhances directional tuning. Our results indicate that spikes are initiated at multiple sites within the dendritic arbors of DSGCs and that each dendritic spike initiates a somatic spike. We propose that dendritic spike failure, produced by local inhibitory inputs, might be a critical factor that enhances directional tuning of somatic spikes.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2012
DOI: 10.1038/NRN3165
Abstract: Visual information is processed in the retina to a remarkable degree before it is transmitted to higher visual centres. Several types of retinal ganglion cells (the output neurons of the retina) respond preferentially to image motion in a particular direction, and each type of direction-selective ganglion cell (DSGC) is comprised of multiple subtypes with different preferred directions. The direction selectivity of the cells is generated by erse mechanisms operating within microcircuits that rely on independent neuronal processing in in idual dendrites of both the DSGCs and the presynaptic neurons that innervate them.
Publisher: Cambridge University Press (CUP)
Date: 11-2004
DOI: 10.1017/S095252380421611X
Abstract: Light-evoked currents were recorded from rod bipolar cells in a dark-adapted mouse retinal slice preparation. Low-intensity light steps evoked a sustained inward current. Saturating light steps evoked an inward current with an initial peak that inactivated, with a time constant of about 60–70 ms, to a steady plateau level that was maintained for the duration of the step. The inactivation was strongest at hyperpolarized potentials, and absent at positive potentials. Inactivation was mediated by an increase in the intracellular calcium concentration, as it was abolished in cells dialyzed with 10 mM BAPTA, but was present in cells dialyzed with 1 mM EGTA. Moreover, responses to brief flashes of light were broader in the presence of intracellular BAPTA indicating that the calcium feedback actively shapes the time course of the light responses. Recovery from inactivation observed for paired-pulse stimuli occurred with a time constant of about 375 ms. Calcium feedback could act to increase the dynamic range of the bipolar cells, and to reduce variability in the litude and duration of the single-photon signal. This may be important for nonlinear processing at downstream sites of convergence from rod bipolar cells to AII amacrine cells. A model in which intracellular calcium rapidly binds to the light-gated channel and reduces the conductance can account for the results.
Publisher: Public Library of Science (PLoS)
Date: 19-08-2010
Publisher: Wiley
Date: 05-2000
DOI: 10.1111/J.1469-7793.2000.00879.X
Abstract: Voltage-cl and current-cl recordings were made from bipolar cells in dark-adapted mouse retinal slices. Light-evoked responses fell into three groups corresponding to the rod bipolar cells, on-cone bipolar cells and off-cone bipolar cells. The morphology of the recorded cells confirmed this classification. Intensity-response relations were well fitted by a Michaelis saturation function with Hill coefficients of 1.15 +/- 0.11 (n = 6) for rod bipolar cells and 2.33 +/- 0.06 (n = 4) for cone inputs onto on-cone bipolar cells. In the absence of antagonists for GABA or glycine receptors, light-evoked synaptic currents for all cells displayed linear current-voltage relations that reversed near 0 mV, indicating that very little inhibition was activated under dark-adapted recording conditions. Saturating light stimuli evoked conductances of 0.81 +/- 0.56 nS (n = 4) in rod bipolar cells and 1.1 +/- 0.8 nS (n = 4) in on-cone bipolar cells. Receptive field widths were estimated by flashing a vertical light bar at various locations along the slice. Rod and on-cone bipolar cells had receptive field widths of 67 +/- 16 micrometer (n = 6) and 43 +/- 7 microm (n = 5), respectively. The maximum spatial resolution of an array of such cone bipolar cells was estimated to be 0.3 cycles deg-1, compared with a maximum resolution of 0.5 cycles deg-1 obtained from behavioural studies in mice. Our results suggest that this limit to spatial resolution could be imposed early in the visual system by the size of the bipolar cell receptive fields.
Publisher: Cambridge University Press (CUP)
Date: 2012
DOI: 10.1017/S0952523811000393
Abstract: Starburst amacrine cells (SBACs) within the adult mammalian retina provide the critical inhibition that underlies the receptive field properties of direction-selective ganglion cells (DSGCs). The SBACs generate direction-selective output of GABA that differentially inhibits the DSGCs. We review the biophysical mechanisms that produce directional GABA release from SBACs and test a network model that predicts the effects of reciprocal inhibition between adjacent SBACs. The results of the model simulations suggest that reciprocal inhibitory connections between closely spaced SBACs should be spatially selective, while connections between more widely spaced cells could be indiscriminate. SBACs were initially identified as cholinergic neurons and were subsequently shown to contain release both acetylcholine and GABA. While the role of the GABAergic transmission is well established, the role of the cholinergic transmission remains unclear.
Publisher: Wiley
Date: 29-03-2017
DOI: 10.1002/CNE.24207
Publisher: Society for Neuroscience
Date: 17-11-2010
DOI: 10.1523/JNEUROSCI.2081-10.2010
Abstract: Cells sensitive to the orientation of edges are ubiquitous in visual systems, and have been described in the vertebrate retina, yet the synaptic mechanisms that generate orientation selectivity in the retina are largely unknown. Here, we analyze the synaptic mechanisms that generate selective responses to vertically and horizontally oriented stimuli in rabbit retinal ganglion cells. The data indicate that the excitatory and inhibitory inputs to orientation-selective ganglion cells are rendered orientation selective within the presynaptic circuitry. In accordance with previous extracellular recordings, presynaptic GABAergic inhibition is critical to generate orientation selectivity, and we show that it includes lateral inhibition of glutamatergic bipolar cells and serial inhibitory connections between GABAergic and glycinergic amacrine cells. Despite very similar spiking properties, vertically and horizontally selective ganglion cells (VS-GCs and HS-GCs, respectively) show marked differences in their underlying synaptic mechanisms. Both cell types receive glutamatergic inputs via non-NMDA (AMPA/kainate) and NMDA receptors, while VS-GCs receive additional excitation mediated by glycinergic disinhibition. A striking difference between these cells is that during nonpreferred simulation, excitation is suppressed and direct glycinergic inhibition is increased in HS-GCs, whereas for VS-GCs, both excitatory and inhibitory inputs are suppressed. Thus, orientation selectivity is generated presynaptically both by modulation of bipolar cell output and by serial inhibitory connections between amacrine cells. Minimal circuit models are proposed that account for these observations.
Publisher: Cambridge University Press (CUP)
Date: 07-2004
DOI: 10.1017/S0952523804214109
Abstract: The starburst amacrine cell (SBAC), found in all mammalian retinas, is thought to provide the directional inhibitory input recorded in On–Off direction-selective ganglion cells (DSGCs). While voltage recordings from the somas of SBACs have not shown robust direction selectivity (DS), the dendritic tips of these cells display direction-selective calcium signals, even when γ-aminobutyric acid (GABA a,c ) channels are blocked, implying that inhibition is not necessary to generate DS. This suggested that the distinctive morphology of the SBAC could generate a DS signal at the dendritic tips, where most of its synaptic output is located. To explore this possibility, we constructed a compartmental model incorporating realistic morphological structure, passive membrane properties, and excitatory inputs. We found robust DS at the dendritic tips but not at the soma. Two-spot apparent motion and annulus radial motion produced weak DS, but thin bars produced robust DS. For these stimuli, DS was caused by the interaction of a local synaptic input signal with a temporally delayed “global” signal, that is, an excitatory postsynaptic potential (EPSP) that spread from the activated inputs into the soma and throughout the dendritic tree. In the preferred direction the signals in the dendritic tips coincided, allowing summation, whereas in the null direction the local signal preceded the global signal, preventing summation. Sine-wave grating stimuli produced the greatest amount of DS, especially at high velocities and low spatial frequencies. The sine-wave DS responses could be accounted for by a simple mathematical model, which summed phase-shifted signals from soma and dendritic tip. By testing different artificial morphologies, we discovered DS was relatively independent of the morphological details, but depended on having a sufficient number of inputs at the distal tips and a limited electrotonic isolation. Adding voltage-gated calcium channels to the model showed that their threshold effect can lify DS in the intracellular calcium signal.
Publisher: Society for Neuroscience
Date: 20-12-2006
DOI: 10.1523/JNEUROSCI.1991-06.2006
Abstract: Visual acuity is limited by the size and density of the smallest retinal ganglion cells, which correspond to the midget ganglion cells in primate retina and the β-ganglion cells in cat retina, both of which have concentric receptive fields that respond at either light-On or light-Off. In contrast, the smallest ganglion cells in the rabbit retina are the local edge detectors (LEDs), which respond to spot illumination at both light-On and light-Off. However, the LEDs do not predominate in the rabbit retina and the question arises, what role do they play in fine spatial vision? We studied the morphology and physiology of LEDs in the isolated rabbit retina and examined how their response properties are shaped by the excitatory and inhibitory inputs. Although the LEDs comprise only ∼15% of the ganglion cells, neighboring LEDs are separated by 30–40 μm on the visual streak, which is sufficient to account for the grating acuity of the rabbit. The spatial and temporal receptive-field properties of LEDs are generated by distinct inhibitory mechanisms. The strong inhibitory surround acts presynaptically to suppress both the excitation and the inhibition elicited by center stimulation. The temporal properties, characterized by sluggish onset, sustained firing, and low bandwidth, are mediated by the temporal properties of the bipolar cells and by postsynaptic interactions between the excitatory and inhibitory inputs. We propose that the LEDs signal fine spatial detail during visual fixation, when high temporal frequencies are minimal.
Publisher: Public Library of Science (PLoS)
Date: 27-08-2010
Publisher: Society for Neuroscience
Date: 16-03-2016
DOI: 10.1523/JNEUROSCI.1432-15.2016
Abstract: Neurons that signal the orientation of edges within the visual field have been widely studied in primary visual cortex. Much less is known about the mechanisms of orientation selectivity that arise earlier in the visual stream. Here we examine the synaptic and morphological properties of a subtype of orientation-selective ganglion cell in the rabbit retina. The receptive field has an excitatory ON center, flanked by excitatory OFF regions, a structure similar to simple cell receptive fields in primary visual cortex. Examination of the light-evoked postsynaptic currents in these ON-type orientation-selective ganglion cells (ON-OSGCs) reveals that synaptic input is mediated almost exclusively through the ON pathway. Orientation selectivity is generated by larger excitation for preferred relative to orthogonal stimuli, and conversely larger inhibition for orthogonal relative to preferred stimuli. Excitatory orientation selectivity arises in part from the morphology of the dendritic arbors. Blocking GABA A receptors reduces orientation selectivity of the inhibitory synaptic inputs and the spiking responses. Negative contrast stimuli in the flanking regions produce orientation-selective excitation in part by disinhibition of a tonic NMDA receptor-mediated input arising from ON bipolar cells. Comparison with earlier studies of OFF-type OSGCs indicates that erse synaptic circuits have evolved in the retina to detect the orientation of edges in the visual input. SIGNIFICANCE STATEMENT A core goal for visual neuroscientists is to understand how neural circuits at each stage of the visual system extract and encode features from the visual scene. This study documents a novel type of orientation-selective ganglion cell in the retina and shows that the receptive field structure is remarkably similar to that of simple cells in primary visual cortex. However, the data indicate that, unlike in the cortex, orientation selectivity in the retina depends on the activity of inhibitory interneurons. The results further reveal the physiological basis for feature detection in the visual system, elucidate the synaptic mechanisms that generate orientation selectivity at an early stage of visual processing, and illustrate a novel role for NMDA receptors in retinal processing.
Publisher: Society for Neuroscience
Date: 30-10-2018
DOI: 10.1523/JNEUROSCI.1784-18.2018
Abstract: The ability to detect moving objects is an ethologically salient function. Direction-selective neurons have been identified in the retina, thalamus, and cortex of many species, but their homology has remained unclear. For instance, it is unknown whether direction-selective retinal ganglion cells (DSGCs) exist in primates and, if so, whether they are the equivalent to mouse and rabbit DSGCs. Here, we used a molecular/circuit approach in both sexes to address these issues. In mice, we identify the transcription factor Satb2 (special AT-rich sequence-binding protein 2) as a selective marker for three RGC types: On–Off DSGCs encoding motion in either the anterior or posterior direction, a newly identified type of Off-DSGC, and an Off-sustained RGC type. In rabbits, we find that expression of Satb2 is conserved in On–Off DSGCs however, it has evolved to include On–Off DSGCs encoding upward and downward motion in addition to anterior and posterior motion. Next, we show that macaque RGCs express Satb2 most likely in a single type. We used rabies virus-based circuit-mapping tools to reveal the identity of macaque Satb2-RGCs and discovered that their dendritic arbors are relatively large and monostratified. Together, these data indicate Satb2-expressing On–Off DSGCs are likely not present in the primate retina. Moreover, if DSGCs are present in the primate retina, it is unlikely that they express Satb2. SIGNIFICANCE STATEMENT The ability to detect object motion is a fundamental feature of almost all visual systems. Here, we identify a novel marker for retinal ganglion cells encoding directional motion that is evolutionarily conserved in mice and rabbits, but not in primates. We show in macaque monkeys that retinal ganglion cells (RGCs) that express this marker comprise a single type and are morphologically distinct from mouse and rabbit direction-selective RGCs. Our findings indicate that On–Off direction-selective retinal neurons may have evolutionarily erged in primates and more generally provide novel insight into the identity and organization of primate parallel visual pathways.
Publisher: Wiley
Date: 09-1990
DOI: 10.1113/JPHYSIOL.1990.SP018206
Abstract: 1. Cells in the ganglion cell layer of salamander retinal slices were voltage cl ed using patch pipettes. Light elicited transient excitatory postsynaptic currents (EPSCs) in on-off ganglion cells and sustained EPSCs in on ganglion cells. Light-evoked inhibitory postsynaptic currents in these cells could be blocked by 100 microM-bicuculline methobromide and 500 nM-strychnine. 2. In the presence of external Cd2+, at a concentration that blocked light-evoked synaptic inputs, N-methyl-D-aspartate (NMDA) and the non-NMDA-receptor agonists, quisqualate and kainate, gated conductances in both on-off and on ganglion cells. The current-voltage (I-V) curve for the conductance elicited by NMDA had a negative slope between -40 and -70 mV and a reversal potential near 0 mV. The I-V curves for the non-NMDA-receptor-mediated conductances were nearly linear and also had reversal potentials near 0 mV. 3. I-V curves were measured at an early time point near the peak of transient EPSCs and at a later time point during the decay phase of the responses. The late I-V curve had a negative slope below -40 mV. The early I-V curve had a positive slope over the entire voltage range but the slope was greater at positive than at negative potentials. The evoked current reversed near 0 mV at both time points. 4. The region of negative slope of the late I-V curve was eliminated when Mg2+ was removed from the external saline. A slowly decaying component of transient EPSCs was eliminated in 20 microM-DL-2-amino-7-phosphonoheptanoate (AP7), an NMDA-receptor antagonist. 5. Application of 1 microM-6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA-receptor antagonist at this concentration, blocked a fast component of transient EPSCs. 6. Our results demonstrate that the synaptic inputs to on-off ganglion cells have two components: a slower NMDA-receptor-mediated component having a time-to-peak of 110 +/- 45 ms and an e-fold decay time of 209 +/- 35 ms at -31 mV (mean +/- S.D., n = 5), and a faster non-NMDA-receptor-mediated component having a time-to-peak of 28 +/- 10 ms and an e-fold decay time of 43 +/- 20 ms at -31 mV (n = 8). 7. A similar analysis of sustained EPSCs of on ganglion cells showed that these currents resulted from sustained activation of both NMDA and non-NMDA receptors.
Publisher: Cambridge University Press (CUP)
Date: 03-1999
DOI: 10.1017/S0952523899162096
Abstract: Patch-cl recordings were made from ganglion cells in an in vitro dark-adapted rabbit retina preparation. Cells were stimulated by images generated on a computer monitor and focussed onto the photoreceptors. Excitatory inward currents were recorded in response to spot stimuli centered on the somas of the recorded cells. Center illumination of on-brisk-transient cells produced large transient excitatory postsynaptic currents (EPSCs) which were invariably followed by a small steady-state inward component. Illumination of a centered annulus failed to elicit the transient EPSC. Simultaneous illumination of the annulus and the center spot blocked the large transient EPSC, consistent with activation of an inhibitory surround. Application of tetrodotoxin (TTX), which blocks sodium-dependent action potentials, also blocked the surround inhibition in ON-brisk transient cells as well as some other classes of ganglion cells. It is concluded that, in some ganglion cell classes, the surround is generated largely through the activity of spiking neurons, and it is suggested that the amacrine cells in the inner plexiform layer are involved.
Publisher: Springer Science and Business Media LLC
Date: 12-12-1997
Abstract: Glutamate is the major excitatory neurotransmitter of the mammalian retina and glutamate uptake is essential for normal transmission at glutamatergic synapses. The reverse transcriptase-polymerase chain reaction (RT-PCR) has revealed the presence of three different high-affinity glutamate transporters in the rat retina, viz. GLAST-1, GLT-1 and EAAC-1. No message has been found in the retina for EAAT-4, a transporter recently cloned from human brain. By using membrane vesicle preparations of total rat retina, we show that glutamate uptake in the retina is a high-affinity electrogenic sodium-dependent transport process driven by the transmembrane sodium ion gradient. Autoradiography of intact and dissociated rat retinae indicates that glutamate uptake by Müller glial cells dominates total retinal glutamate transport and that this uptake is strongly influenced by the activity of glutamine synthetase. RT-PCR, immunoblotting and immunohistochemistry have revealed that Müller cells express only GLAST-1. The Km for glutamate of GLAST-1 is 2.1+/-0.4 microM. This study suggests a major role for the Müller cell glutamate transporter GLAST-1 in retinal transmitter clearance. By regulating the extracellular glutamate concentration, the action of GLAST-1 in Müller cells may extend beyond the protection of neurons from excitotoxicity we suggest a mechanism by which Müller cell glutamate transport might play an active role in shaping the time course of excitatory transmission in the retina.
Publisher: Wiley
Date: 12-1986
DOI: 10.1111/J.1476-5381.1986.TB11170.X
Abstract: Calcium and potassium currents were examined in dialysed, isolated dorsal root ganglion neurones of the cat by use of a single electrode voltage cl . Two calcium currents were identified, a low threshold inactivating (transient) current and a higher threshold slowly inactivating (sustained) current. Both currents were blocked by 1 mM cadmium and replacement of calcium with manganese, which revealed an underlying nonspecific outward current. The sustained current disappeared with internal dialysis over a period of 20 to 30 min. (-)-Baclofen (100 microM) and gamma-aminobutyric acid (GABA, 100 microM) were found to reduce the peak litude of the sustained calcium current, an effect which became more pronounced with increasing concentrations of external magnesium (1-5 mM). In 5 mM external magnesium, 100 microM baclofen reduced the calcium current by 28%. The voltage-activated delayed rectifier appeared to be the most prominent potassium current in these cells. We were unable to find any evidence for a significant contribution from calcium-activated potassium conductance or a transient potassium conductance under our recording conditions. Baclofen and GABA at 100 microM had no consistent effect on the voltage-activated potassium current. Baclofen did not change the resting potassium conductance.
Publisher: Wiley
Date: 12-1988
DOI: 10.1113/JPHYSIOL.1988.SP017424
Abstract: 1. Instantaneous current-voltage (I-V) relations were measured from tail currents with 10 mM-external calcium at 20 degrees C. The I-V relations had a lower potential dependence than predicted by the Goldman-Hodgkin-Katz constant-field equation. Previously proposed symmetric two-site three-barrier (2S3B) rate theory models were able to account for the I-V relations reasonably well. 2. Reversal of the current flow through the calcium channels was recorded using 10 mM-barium internally and 20 mM-barium externally. The channels appeared to rectify at positive potentials, a property not consistent with symmetric rate theory models. 3. Externally applied cadmium ions blocked the calcium channels through at least two sites. One high-affinity blocking site was located within the membrane electric field and had a dissociation constant of around 16 microM at O mV. Cadmium block at this site was relieved with hyperpolarization with a voltage dependence equivalent to a alent cation moving through about 75% of the membrane electric field. 4. A low-affinity potential-independent blocking site also appeared to be present, having a dissociation constant of around 106 microM. 5. Cadmium had significant effects on the tail current kinetics at potentials close to 0 mV, presumably due to slow unblocking events. The rate at which cadmium ions left the calcium channel free to conduct was estimated to be about 3300 s-1 at +10 mV.
Publisher: Wiley
Date: 12-1988
DOI: 10.1113/JPHYSIOL.1988.SP017423
Abstract: 1. The kinetics of the sustained calcium current were examined in cat dorsal root ganglion (DRG) neurones, using a two-suction-electrode voltage cl . It was shown that this current could be examined with minimal contamination from other ionic currents. Experiments were performed at 20 degrees C, with a concentration of 10 mM-calcium externally. 2. The transient calcium current was eliminated by using a holding potential of -50 mV. The sustained calcium current showed no evidence of steady-state inactivation at potentials between -90 and -30 mV. 3. The activation and deactivation time course of the calcium current was described by a double-exponential function. The activation process was examined without interference from significant inactivation under the conditions used. 4. The steady-state activation of the calcium channels was approximated by a two-step activation process. Both reactions were voltage sensitive, the first having an equivalent valency of 3.4 +/- 0.1 electronic charges (e-), and the second with an equivalent valency of 1.0 +/- 0.2 e-. On average, half-maximal channel activation occurred at +10 mV. 5. The fast and the slow time constants of the exponential relaxations differed by a factor of 4-10 and both showed significant voltage dependence. Both the fast and slow time constants were greatest at potentials where approximately half the available channels were activated in the steady state. The slow time constant measured from activation and deactivation appeared to be independent of the starting potential. 6. The fractional litude of the slow exponential component of the tail currents was 0.09 +/- 0.01 at -70 mV and increased steadily at more positive potentials passing through a clear maximum of 0.59 +/- 0.03 at -10 mV. 7. Reducing the temperature decreased the magnitude of the peak inward current, with an apparent activation energy (Ea) of 67 kJ/mol. The slow time constants measured from activation and deactivation were also reduced at lower temperatures. The slow activation time constant had a higher temperature sensitivity (Ea = 85 kJ/mol) than the slow tail current time constant (Ea = 29 kJ/mol). The fast tail current time constant was reduced at lower temperatures with an apparent Ea of 79 kJ/mol. 8. Application of 10 microM-(+/-)Bay K 8644 prolonged the tail currents and shortened the activation time constant. The calcium current was activated at more negative potentials and the slope of the steady-state activation curve was reduced.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: Cambridge University Press (CUP)
Date: 09-2004
DOI: 10.1017/S0952523804215048
Abstract: At very low light levels the sensitivity of the visual system is determined by the efficiency with which single photons are captured, and the resulting signal transmitted from the rod photoreceptors through the retinal circuitry to the ganglion cells and on to the brain. Although the tiny electrical signals due to single photons have been observed in rod photoreceptors, little is known about how these signals are preserved during subsequent transmission to the optic nerve. We find that the synaptic currents elicited by single photons in mouse rod bipolar cells have a peak litude of 5–6 pA, and that about 20 rod photoreceptors converge upon each rod bipolar cell. The data indicates that the first synapse, between rod photoreceptors and rod bipolar cells, signals a binary event: the detection, or not, of a photon or photons in the connected rod photoreceptors. We present a simple model that demonstrates how a threshold nonlinearity during synaptic transfer allows transmission of the single photon signal, while rejecting the convergent neural noise from the 20 other rod photoreceptors feeding into this first synapse.
Publisher: Cambridge University Press (CUP)
Date: 11-2003
DOI: 10.1017/S0952523803206040
Abstract: Light-evoked synaptic currents were recorded from on-cone bipolar cells in the mouse retina. Fluctuations in the synaptic current observed during maintained light steps were analyzed in order to estimate the litude of the underlying unitary event. The maximal synaptic current variance was 5-fold larger than the maximum expected from fluctuations in the number of active postsynaptic channels. Due to uncertainty in the contribution from channel variance, we calculated a range of values for the unitary event litude. The observed variance could be accounted for if 30–39 synaptic sites randomly generated unitary events with a waveform identical to the flash-response, and an litude of −3.1 to −2.4 pA. The litude is consistent with gating about five mGluR6 channels. The shape of the variance–mean relation suggests that in bright light transmitter release approaches zero, while in darkness transmitter release saturates the postsynaptic response. Thus the on-cone bipolar cell synapse is operating over its entire possible range. If it is assumed that the postsynaptic response saturates when one unitary event occurs per integration time, then a lower bound for the unitary event rate is 18 events/s/synaptic site. If the unitary event is generated by a single synaptic vesicle, the results suggest the total vesicle cycling rate available for encoding the on-cone bipolar cell signal is about 540–700 s −1 .
Publisher: Cambridge University Press (CUP)
Date: 05-2009
DOI: 10.1017/S0952523809990137
Abstract: There are two subclasses of alpha cell in the mammalian retina, which are morphologically identical in plain view but have opposite responses to a luminance change: one is ON center and the other is OFF center. Recent studies have shown that the neural circuitries, which underlie light responses in such ON- and OFF-ganglion cell pairs, are not mirror symmetric with respect to the ON and OFF pathways (Pang et al., 2003 Zaghloul et al., 2003 Murphy & Rieke, 2006). This study examines alpha-cell homologues in the mouse retina and elucidates the synaptic mechanisms that generate their light responses. Morphological analysis of recorded cells revealed three subclasses that were essentially identical in plan view but had distinct vertical stratification levels. We refer to these cells as the sustained ON (ON-S), sustained OFF (OFF-S), and transient OFF (OFF-T) cells (Murphy & Rieke, 2006 Margolis & Detwiler, 2007). Both ON-S and OFF-S cells were largely driven through the ON pathway via changes in excitatory and inhibitory inputs, respectively. Light responses of OFF-T cells were driven by transient changes in excitatory and inhibitory inputs. Light responses of OFF-S cells were also measured in connexin 36 knockout mice in order to dissect glycinergic input arising from AII amacrine cells. At photopic/mesopic intensities, peak glycinergic input to OFF-S cells in the connexin 36 knockout mouse was reduced by ~85% compared to OFF-S cells in the wild-type retina. This is consistent with the idea that AII cells receive their input from ON-cone bipolar cells through gap junctions and in turn provide glycinergic inhibition to OFF-S cells.
Publisher: Society for Neuroscience
Date: 09-10-2013
DOI: 10.1523/JNEUROSCI.1249-13.2013
Abstract: In the primate visual system, the ganglion cells of the magnocellular pathway underlie motion and flicker detection and are relatively transient, while the more sustained ganglion cells of the parvocellular pathway have comparatively lower temporal resolution, but encode higher spatial frequencies. Although it is presumed that functional differences in bipolar cells contribute to the tuning of the two pathways, the properties of the relevant bipolar cells have not yet been examined in detail. Here, by making patch-cl recordings in acute slices of macaque retina, we show that the bipolar cells within the magnocellular pathway, but not the parvocellular pathway, exhibit voltage-gated sodium (Na V ), T-type calcium (Ca V ), and hyperpolarization-activated, cyclic nucleotide-gated (HCN) currents, and can generate action potentials. Using immunohistochemistry in macaque and human retinae, we show that Na V 1.1 is concentrated in an axon initial segment (AIS)-like region of magnocellular pathway bipolar cells, a specialization not seen in transient bipolar cells of other vertebrates. In contrast, Ca V 3.1 channels were localized to the somatodendritic compartment and proximal axon, but were excluded from the AIS, while HCN1 channels were concentrated in the axon terminal boutons. Simulations using a compartmental model reproduced physiological results and indicate that magnocellular pathway bipolar cells initiate spikes in the AIS. Finally, we demonstrate that Na V channels in bipolar cells augment excitatory input to parasol ganglion cells of the magnocellular pathway. Overall, the results demonstrate that selective expression of voltage-gated channels contributes to the establishment of parallel processing in the major visual pathways of the primate retina.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2010
Publisher: Proceedings of the National Academy of Sciences
Date: 08-03-2010
Abstract: Retinal ganglion cells convey information by increasing their firing in response to an optimal visual stimulus or “trigger feature.” However, one class of ganglion cell responds to changes in the visual scene by decreasing its firing. These cells, termed uniformity detectors in the rabbit retina, are encountered only rarely and the synaptic mechanisms underlying their unusual responses have not been investigated. In this study, patch-cl recordings of uniformity detectors show that the action potentials underlying the maintained firing arise within “complex spikes.” Both ON and OFF visual stimuli elicit only inhibitory synaptic input, the immediate effect of which is to suppress the maintained firing. However, this inhibition also alters the properties of the “renascent” spiking by increasing the litude of the spikes within each burst, suggesting that the effect may increase the efficacy of spike propagation and transmission.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 29-09-2000
DOI: 10.1126/SCIENCE.289.5488.2347
Abstract: Direction-selective ganglion cells (DSGCs) in the retina respond strongly when stimulated by image motion in a preferred direction but are only weakly excited by image motion in the opposite null direction. Such coding represents an early manifestation of complex information processing in the visual system, but the cellular locus and the synaptic mechanisms have yet to be elucidated. We recorded the synaptic activity of DSGCs using strategies to observe the asymmetric inhibitory inputs that underlie the generation of direction selectivity. The critical nonlinear interactions between the excitatory and inhibitory inputs took place postsynaptically within the dendrites of the DSGCs.
Publisher: Society for Neuroscience
Date: 30-09-2015
DOI: 10.1523/JNEUROSCI.1712-15.2015
Abstract: Much of the computational power of the retina derives from the activity of amacrine cells, a large and erse group of GABAergic and glycinergic inhibitory interneurons. Here, we identify an ON-type orientation-selective, wide-field, polyaxonal amacrine cell (PAC) in the rabbit retina and demonstrate how its orientation selectivity arises from the structure of the dendritic arbor and the pattern of excitatory and inhibitory inputs. Excitation from ON bipolar cells and inhibition arising from the OFF pathway converge to generate a quasi-linear integration of visual signals in the receptive field center. This serves to suppress responses to high spatial frequencies, thereby improving sensitivity to larger objects and enhancing orientation selectivity. Inhibition also regulates the magnitude and time course of excitatory inputs to this PAC through serial inhibitory connections onto the presynaptic terminals of ON bipolar cells. This presynaptic inhibition is driven by graded potentials within local microcircuits, similar in extent to the size of single bipolar cell receptive fields. Additional presynaptic inhibition is generated by spiking amacrine cells on a larger spatial scale covering several hundred microns. The orientation selectivity of this PAC may be a substrate for the inhibition that mediates orientation selectivity in some types of ganglion cells. SIGNIFICANCE STATEMENT The retina comprises numerous excitatory and inhibitory circuits that encode specific features in the visual scene, such as orientation, contrast, or motion. Here, we identify a wide-field inhibitory neuron that responds to visual stimuli of a particular orientation, a feature selectivity that is primarily due to the elongated shape of the dendritic arbor. Integration of convergent excitatory and inhibitory inputs from the ON and OFF visual pathways suppress responses to small objects and fine textures, thus enhancing selectivity for larger objects. Feedback inhibition regulates the strength and speed of excitation on both local and wide-field spatial scales. This study demonstrates how different synaptic inputs are regulated to tune a neuron to respond to specific features in the visual scene.
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1016/J.VISRES.2004.07.043
Abstract: Mammals can see at low scotopic light levels where only 1 rod in several thousand transduces a photon. The single photon signal is transmitted to the brain by the ganglion cell, which collects signals from more than 1000 rods to provide enough lification. If the system were linear, such convergence would increase the neural noise enough to overwhelm the tiny rod signal. Recent studies provide evidence for a threshold nonlinearity in the rod to rod bipolar synapse, which removes much of the background neural noise. We argue that the height of the threshold should be 0.85 times the litude of the single photon signal, consistent with the saturation observed for the single photon signal. At this level, the rate of false positive events due to neural noise would be masked by the higher rate of dark thermal events. The evidence presented suggests that this synapse is optimized to transmit the single photon signal at low scotopic light levels.
Publisher: Wiley
Date: 29-06-2016
DOI: 10.1113/JP272384
Publisher: Elsevier BV
Date: 10-2011
Publisher: American Physiological Society
Date: 08-2015
Abstract: Direction-selective ganglion cells (DSGCs) respond selectively to motion toward a “preferred” direction, but much less to motion toward the opposite “null” direction. Directional signals in the DSGC depend on GABAergic inhibition and are observed over a wide range of speeds, which precludes motion detection based on a fixed temporal correlation. A voltage-cl analysis, using narrow bar stimuli similar in width to the receptive field center, demonstrated that inhibition to DSGCs saturates rapidly above a threshold contrast. However, for wide bar stimuli that activate both the center and surround, inhibition depends more linearly on contrast. Excitation for both wide and narrow bars was also more linear. We propose that positive feedback, likely within the starburst amacrine cell or its network, produces steep saturation of inhibition at relatively low contrast. This mechanism renders GABA release essentially contrast and speed invariant, which enhances directional signals for small objects and thereby increases the signal-to-noise ratio for direction-selective signals in the spike train over a wide range of stimulus conditions. The steep saturation of inhibition confers to a neuron immunity to noise in its spike train, because when inhibition is strong no spikes are initiated.
Publisher: Public Library of Science (PLoS)
Date: 21-02-2014
Publisher: Society for Neuroscience
Date: 25-07-2023
DOI: 10.1523/ENEURO.0158-23.2023
Abstract: AMPA receptors (AMPARs) are the major mediators of fast excitatory neurotransmission in the retina as in other parts of the brain. In most neurons, the synaptic targeting, pharmacology, and function of AMPARs are influenced by auxiliary subunits including the transmembrane AMPA receptor regulatory proteins (TARPs). However, it is unclear which TARP subunits are present at retinal synapses and how they influence receptor localization and function. Here, we show that TARPɣ2 (stargazin) is associated with AMPARs in the synaptic layers of the mouse, rabbit, macaque, and human retina. In most species, TARPɣ2 expression was high where starburst amacrine cells (SACs) ramify and transcriptomic analyses suggest correspondingly high gene expression in mouse and human SACs. Synaptic expression of GluA2, GluA3, and GluA4 was significantly reduced in a mouse mutant lacking TARPɣ2 expression (stargazer mouse stg ), whereas GluA1 levels were unaffected. AMPAR-mediated light-evoked EPSCs in ON-SACs from stg mice were ∼30% smaller compared with heterozygous littermates. There was also loss of a transient ON pathway-driven GABAergic input to ON-SACs in stg mutants. Direction-selective ganglion cells in the stg mouse showed normal directional tuning, but their surround inhibition and thus spatial tuning was reduced. Our results indicate that TARPɣ2 is required for normal synaptic expression of GluA2, GluA3, and GluA4 in the inner retina. The presence of residual AMPAR expression in the stargazer mutant suggests that other TARP subunits may compensate in the absence of TARPɣ2.
Publisher: Elsevier BV
Date: 08-2002
DOI: 10.1016/S0959-4388(02)00337-9
Abstract: The neuronal circuitry underlying the generation of direction selectivity in the retina has remained elusive for almost 40 years. Recent studies indicate that direction selectivity may be established within the radial dendrites of 'starburst' amacrine cells and that retinal ganglion cells may acquire their direction selectivity by the appropriate weighting of excitatory and inhibitory inputs from starburst dendrites pointing in different directions. If so, this would require unexpected complexity and subtlety in the synaptic connectivity of these CNS neurons.
Publisher: American Physiological Society
Date: 04-2012
Abstract: Different types of retinal ganglion cells represent distinct spatiotemporal filters that respond selectively to specific features in the visual input. Much about the circuitry and synaptic mechanisms that underlie such specificity remains to be determined. This study examines how N-methyl-d-aspartate (NMDA) receptor signaling combines with other excitatory and inhibitory mechanisms to shape the output of small-field OFF brisk-sustained ganglion cells (OFF-BSGCs) in the rabbit retina. We used voltage cl to separately resolve NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and inhibitory inputs elicited by stimulation of the receptive field center. Three converging circuits were identified. First is a direct glutamatergic input, arising from OFF cone bipolar cells (CBCs), which is mediated by synaptic NMDA and AMPA receptors. The NMDA input was saturated at 10% contrast, whereas the AMPA input increased monotonically up to 60% contrast. We propose that NMDA inputs selectively enhance sensitivity to low contrasts. The OFF bipolar cells, mediating this direct excitatory input, express dendritic kainate (KA) receptors, which are resistant to the nonselective AMPA/KA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt (NBQX), but are suppressed by a GluK1- and GluK3-selective antagonist, ( S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxy-thiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione (UBP-310). The second circuit entails glycinergic crossover inhibition, arising from ON-CBCs and mediated by AII amacrine cells, which modulate glutamate release from the OFF-CBC terminals. The third circuit also comprises glycinergic crossover inhibition, which is driven by the ON pathway however, this inhibition impinges directly on the OFF-BSGCs and is mediated by an unknown glycinergic amacrine cell that expresses AMPA but not KA receptors.
Publisher: Elsevier BV
Date: 07-2003
Publisher: Wiley
Date: 11-1995
DOI: 10.1111/J.1460-9568.1995.TB00652.X
Abstract: Patch-cl recordings were made from ON starburst cholinergic amacrine cells with somas located in the ganglion cell layer of an isolated, dark-adapted rabbit retina preparation. Light responses were analysed and cell identify was confirmed anatomically. The centre light response had a linear current-voltage relation with a reversal potential close to 0 mV. The receptive field size was similar to the dendritic field size. Cholinergic amacrine cells displayed significant surround inhibition. The receptive field profile consisted of a central excitatory region flanked by an inhibitory surround. The surround attenuated the central response to 36% of the maximum. The surround was probably mediated by a combination of presynaptic and postsynaptic inhibition. Starburst amacrine cells did not display action potentials and the presence of a large, voltage-dependent outward current limited depolarizing responses to a maximum potential of about -40 mV. Light responses were completely suppressed during application of 100 microM D,L-2-amino-4-phosphonobutyric acid (APB), consistent with activation exclusively through rod bipolar cells (on) and ON-cone bipolar cells. In darkness the cells displayed a tonic inward current that could be blocked by 100 microM APB and 2 microM CNQX.
Publisher: Society for Neuroscience
Date: 29-03-2019
DOI: 10.1523/JNEUROSCI.3066-18.2019
Abstract: Two types of mammalian direction-selective ganglion cells (DSGCs), ON and ONOFF, operate over different speed ranges. The directional axes of the ON-DSGCs are thought to align with the axes of the vestibular system and provide sensitivity at rotational velocities that are too slow to activate the semicircular canals. ONOFF-DSGCs respond to faster image velocities. Using natural images that simulate the natural visual inputs to freely moving animals, we show that simulated visual saccades suppress responses in ON-DSGCs but not ONOFF-DSGCs recorded in retinas of domestic rabbits of either gender. Analysis of the synaptic inputs shows that this saccadic suppression results from glycinergic inputs that are specific to ON-DSGCs and are absent in ONOFF-DSGCs. When this glycinergic input is blocked, both cell types respond similarly to visual saccades and display essentially identical speed tuning. The results demonstrate that glycinergic circuits within the retina can produce saccadic suppression of retinal ganglion cell activity. The cell-type-specific targeting of the glycinergic circuits further supports the proposed physiological roles of ON-DSGCs in retinal-image stabilization and of ONOFF-DSGCs in detecting local object motion and signaling optical flow. SIGNIFICANCE STATEMENT In the mammalian retina, ON direction-selective ganglion cells (DSGCs) respond preferentially to slow image motion, whereas ONOFF-DSGCs respond better to rapid motion. The mechanisms producing this different speed tuning remain unclear. Here we show that simulated visual saccades suppress ON-DSGCs, but not ONOFF-DSGCs. This selective saccadic suppression is because of the selective targeting of glycinergic inhibitory synaptic inputs to ON-DSGCs. The different saccadic suppression in the two cell types points to different physiological roles, consistent with their projections to distinct areas within the brain. ON-DSGCs may be critical for providing the visual feedback signals that contribute to stabilizing the image on the retina, whereas ONOFF-DSGCs may be important for detecting the onset of saccades or for signaling optical flow.
Publisher: Wiley
Date: 14-09-2011
DOI: 10.1002/CNE.22720
Publisher: American Physiological Society
Date: 10-2018
Abstract: Cell-intrinsic factors, in conjunction with environmental signals, guide migration, differentiation, and connectivity during early development of neuronal circuits. Within the retina, inhibitory starburst amacrine cells (SBACs) comprise ON types with somas in the ganglion cell layer (GCL) and dendrites stratifying narrowly in the inner half of the inner plexiform layer (IPL) and OFF types with somas in the inner nuclear layer (INL) and dendrites stratifying narrowly in the outer half of the IPL. The transcription factor Sox2 is crucial to this subtype specification. Without Sox2, many ON-type SBACs destined for the GCL settle in the INL while many that reach the GCL develop bistratified dendritic arbors. This study asked whether ON-type SBACs in Sox2-conditional knockout retinas exhibit selective connectivity only with ON-type bipolar cells or their bistratified morphology allows them to connect to both ON and OFF bipolar cells. Physiological data demonstrate that these cells receive ON and OFF excitatory inputs, indicating that the ectopically stratified dendrites make functional synapses with bipolar cells. The excitatory inputs were smaller and more transient in Sox2-conditional knockout compared with wild type however, inhibitory inputs appeared largely unchanged. Thus dendritic stratification, rather than cellular identification, may be the major factor that determines ON vs. OFF connectivity. NEW & NOTEWORTHY Conditional knockout of the transcription factor Sox2 during early embryogenesis converts a monostratifying starburst amacrine cell into a bistratifying starburst cell. Here we show that these bistratifying starburst amacrine cells form functional synaptic connections with both ON and OFF bipolar cells. This suggests that normal ON vs. OFF starburst connectivity may not require distinct molecular specification. Proximity alone may be sufficient to allow formation of functional synapses.
Publisher: Society for Neuroscience
Date: 28-05-2014
DOI: 10.1523/JNEUROSCI.4855-13.2014
Abstract: Visual signals are segregated into parallel pathways at the first synapse in the retina between cones and bipolar cells. Within the OFF pathways of mammals, the selective expression of AMPA or kainate-type glutamate receptors in the dendrites of different OFF-bipolar cell types is thought to contribute to formation of distinct temporal channels. AMPA receptors, with rapid recovery from desensitization, are proposed to transmit high temporal frequency signals, whereas kainate receptors (KARs) are presumed to encode lower temporal frequencies. Here we studied the glutamate receptors expressed by OFF-bipolar cells in slice preparations of macaque monkey retina, where the low (midget arvocellular) and high-frequency (parasol/magnocellular) temporal channels are well characterized. We found that all OFF-bipolar types receive input primarily through KARs and that KAR antagonists block light-evoked input to both OFF-midget and OFF-parasol ganglion cells. KAR subunits were differentially expressed in OFF-bipolar types the diffuse bipolar (DB) cells, DB2 and DB3b, expressed GluK1 and showed transient responses to glutamate and the KAR agonist, ATPA. In contrast, flat midget bipolar, DB1, and DB3a cells lacked GluK1 and showed relatively sustained responses. Finally, we found that the KAR accessory protein, Neto1, is expressed at the base of cone pedicles but is not colocalized with the GluK1 subunit. In summary, the results indicate that transient signaling in the OFF pathway of macaques is not dependent on AMPA receptors and that heterogeneity of KARs and accessory proteins may contribute to the formation of parallel temporal channels.
Publisher: Elsevier BV
Date: 08-2015
Publisher: Wiley
Date: 17-10-2011
Location: United States of America
Location: United States of America
No related grants have been discovered for William Taylor.