• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Neurosci. Author manuscript; available in PMC Aug 10, 2010.
Published in final edited form as:
PMCID: PMC2836865
NIHMSID: NIHMS177004

Mechanisms underlying lateral GABAergic feedback onto rod bipolar cells in rat retina

Abstract

GABAergic feedback inhibition from amacrine cells shapes visual signaling in the inner retina. Rod bipolar cells (RBCs), ON-sensitive cells that depolarize in response to light increments, receive reciprocal GABAergic feedback from A17 amacrine cells and additional GABAergic inputs from other amacrine cells located laterally in the IPL. The circuitry and synaptic mechanisms underlying lateral GABAergic inhibition of RBCs are poorly understood. A-type and ρ subunit-containing (C-type) GABA receptors (GABAARs and GABACRs) mediate both forms of inhibition, but their relative activation during synaptic transmission is unclear, and potential interactions between adjacent reciprocal and lateral synapses have not been explored. Here, we recorded from RBCs in acute slices of rat retina and isolated lateral GABAergic inhibition by pharmacologically ablating A17 amacrine cells. We found that amacrine cells providing lateral GABAergic inhibition to RBCs receive excitatory synaptic input mostly from ON bipolar cells via activation of both Ca2+-impermeable and Ca2+-permeable AMPAR receptors (CP-AMPARs) but not NMDA receptors (NMDARs). Voltage-gated Ca2+ (Cav) channels mediate the majority of Ca2+ influx that triggers GABA release, although CP-AMPARs contribute a small component. The intracellular Ca2+ signal contributing to transmitter release is amplified by Ca2+-induced Ca2+ release (CICR) from intracellular stores via activation of ryanodine receptors (RyRs). Furthermore, lateral non-reciprocal feedback is mediated primarily by GABACRs that are activated independently from receptors mediating reciprocal feedback inhibition. These results illustrate numerous physiological differences that distinguish GABA release at reciprocal and lateral synapses, indicating complex, pathway-specific modulation of RBC signaling.

Keywords: Rod bipolar cell, Feedback inhibition, GABA receptors, amacrine cells, Ca2+ permeable AMPA receptors, intracellular stores and ryanodine receptors

Introduction

Visual signaling in the inner retina is modulated by feedback inhibition from amacrine cells (Kolb and Nelson, 1981; MacNeil and Masland, 1998). Understanding the function of this diverse cell class is necessary to discern the signal processing performed by the inner retinal circuitry. Distinct amacrine cell subtypes make glycinergic and GABAergic inputs onto the axon and synaptic terminals of rod bipolar cells (RBCs), thereby shaping the receptive field properties of RBCs and other neurons downstream in the rod pathway (Euler and Masland, 2000; Volgyi et al., 2002; Cui et al., 2003; Eggers and Lukasiewicz, 2006b; Ivanova et al., 2006; Eggers et al., 2007; Chavez and Diamond, 2008), but the physiological properties of most amacrine cells that connect to RBCs remain poorly understood.

RBCs receive reciprocal feedback (i.e., synaptic input from amacrine cells activated directly by the same RBC) and non-reciprocal, or lateral feedback (synaptic input from amacrine cells activated by other bipolar cells) (Dowling and Boycott, 1966; Sterling and Lampson, 1986; Grunert and Martin, 1991). In the rat retina reciprocal feedback is mediated by A17 amacrine cells (Chavez et al., 2006), but the properties of the amacrine cells providing lateral GABAergic feedback to RBCs are largely unexplored. For example, it is not known whether lateral inhibition is driven by the ON and/or OFF pathway. In addition, it is unclear whether GABA release at lateral feedback synapses is driven by Ca2+ influx through Cav channels, release from intracellular stores, influx through glutamate receptors or some combination of the three.

GABAergic feedback onto RBC terminals is mediated by GABAARs and GABACRs (Fletcher et al., 1998; Koulen et al., 1998a; Lukasiewicz and Shields, 1998). These receptors subtypes are not co-localized at the same synaptic sites (Fletcher et al., 1998; Koulen et al., 1998a), suggesting that they may be activated by distinct GABAergic amacrine cell types (Palmer, 2006). At reciprocal synapses, GABA release from A17s activates GABAARs (Singer and Diamond, 2003; Chavez, et al., 2006), but enhancing GABA release can recruit GABACR activation (Hartveit, 1999; Singer and Diamond, 2003; Vigh and von Gersdorff, 2005). It is unclear whether this emergent GABACR-mediated component results from receptor activation within reciprocal synapses (Fletcher et al., 1998), or spillover activation of GABACRs at non-reciprocal synapses.

Here we recorded lateral GABAergic feedback IPSCs from RBCs in rat retinal slices. We found that GABAergic amacrine cells mediating lateral feedback onto RBCs receive excitatory input mostly from ON bipolar cells via Ca2+-permeable and impermeable AMPARs and use voltage-gated Na+ (Nav) channels to enhance input-output coupling. GABA release from these amacrine cells is triggered by Ca2+ influx through both Cav channels and CP-AMPARs and is enhanced by RyR-mediated CICR. Lateral inhibitory synapses activate primarily GABACRs independently of those GABACRs activated by reciprocal GABA release from A17s, suggesting that reciprocal and lateral inputs target distinct postsynaptic GABACR populations on RBC terminals. These results demonstrate that fundamental physiological differences distinguish reciprocal and lateral GABAergic feedback inhibition to RBCs and suggest that these differences likely underlie the distinct roles they play in the rod pathway.

Material and Methods

Rat retinal slices (210 µM thick) were prepared from Sprague-Dawley rats (postnatal days 17–24) using previously described methods (Chavez et al., 2006; Chavez and Diamond, 2008). Briefly, retinas were isolated and sliced in standard artificial cerebrospinal fluid (ASCF) continuously bubbled with 95 % O2 / 5 % CO2 and containing (mM): 119 NaCl, 26 NaHCO3, 1.25 Na2HPO4, 2.5 KCl, 2.5 CaCl2, 1.5 MgSO4, 10 glucose, 2 Na+-pyruvate and 4 Na+-lactate. Infrared differential interference contrast (IR-DIC) video microscopy was used to target RBCs with the patch electrode. RBCs were first identified by their goblet-shaped somata located in the inner nuclear layer (INL), directly adjacent to the outer plexiform layer (OPL) and were further revealed by fluorescent visualization, using internal solution that included Alexa-488 hydrazide (50 µM; for detail see Chavez and Diamond, 2008).

Once in the microscope recording chamber retinal slices were continuously superfused with ASCF at a rate of 1–2 ml/min. Patch electrodes (8–11 MΩ) contained (mM): 100 Cs Methanesulfonate, 20 TEA-Cl, 10 HEPES, 1.5 BAPTA, 10 Na Phosphocreatine, 4 Mg-ATP, 0.4 Na-GTP, 10 glutamic acid; pH 7.4. RBCs generally exhibited high input resistance (≥ 1 GΩ; Singer and Diamond, 2003; Chavez and Diamond, 2008). All experiments, except where noted, were performed at room temperature using ASCF that was supplemented with strychnine (3 µM), to block glycinergic feedback (Cui et al., 2003; Chavez and Diamond, 2008) and 5,7-dihydroxytryptamine (50 µM; DHT), a neurotoxic serotonin analog that ablates A17 amacrine cells and eliminates GABAergic reciprocal feedback (Dong and Hare, 2003; Chavez et al., 2006). The effects of exogenous application of pharmacological reagents were analyzed as previously described (Chavez and Diamond, 2008). All drugs were obtained from Sigma (St. Louis, MO) and Tocris (Ballwin, MO), except TTX (Alomone Labs), Alexa-488 (Molecular Probes, Eugene, USA), and 1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-3,4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 53655; a gift from Dr. John Isaac).

Unless otherwise indicated, RBCs were voltage clamped at 0 mV (the reversal potential for excitatory inputs) and puff application of l-glutamate (50 µM, 25 ms, 1 bar) in the innermost part of IPL was used to elicit synaptic release from amacrine cells onto RBCs. In addition, (RS)-α-cyclopropyl-4-phosphonophenylglyicne (CPPG; 600 µM, 300 ms, 1.5 bar) or kainic acid (kainate; 100 µM, 350–400 ms, 1.5 bar) was puffed into the OPL (~80–100 µm laterally from the recorded RBC) to activate ON and OFF bipolar cells, respectively (Chavez and Diamond, 2008). In these experiments, a group III mGluR agonist (L-AP-4, 10 µM) was included in the ACSF. All puffed agents were applied using a Picospritzer II (General Valve, Fairfield, NJ) connected to a patch pipette (resistance ~8–10 MΩ). Puffing solution was similar to control ACSF, but also contained the stimulating agent (e.g., glutamate) and was pH-buffered with HEPES (10 mM). Puff application of HEPES-buffered ACSF did not evoke detectable responses in RBCs (data not shown). To measure the spatial extent of lateral GABAergic inhibition to RBCs, the glutamate-containing pipette was moved laterally in the IPL as previously described (Chavez and Diamond, 2008). Briefly, three responses were recorded at various positions within the IPL; to control for rundown after each series the pipette was returned to 0 µm and three additional responses were averaged and compared to the initial responses obtained at the beginning of the experiment. Cells exhibiting significant change (≥ 10%) in the 0 µm response were discarded from the analysis. Peak responses at each position were normalized to that recorded at 0 µm in control solution and plotted as a function of distance from the RBC terminal (Figure 1).

Figure 1
Spatial profile of reciprocal and lateral feedback inhibition to RBCs

GABAergic feedback IPSCs were elicited at 14–20 sec intervals, filtered at 2 kHz and sampled at 10 kHz by an ITC-18 analog-to-digital board (InstruTECH) controlled by software written in Igor Pro (Wavemetrics). Glutamate-evoked IPSC amplitudes were measured as the difference between the response peak and the baseline preceding stimulation, whereas reciprocal feedback IPSCs were evoked by a 50 mV depolarizing-step in the RBC (vIPSC; Fig 6) and the peak response was measured as previously described (Chavez et al., 2006). The slow and sustained GABACR-mediated IPSC component (Figure 6) was measured by averaging the last 10–15 ms of the current response. Unless otherwise indicated, statistical comparisons were made with a paired, two-tailed Student’s t test (Igor Pro) and significance was concluded when p<0.05. Within figures, *indicates p<0.05, ** indicates p<0.01 and *** indicates p<0.001, and the number of experiments (n) is indicated in parentheses. Data are presented as mean ± SD, and illustrated traces are averages of 3–20 responses.

Figure 6
GABACR populations activated at lateral and reciprocal feedback synapses are distinct

Results

Lateral GABAergic inputs require Nav channels

Many amacrine cells use Nav-mediated action potentials to enhance signaling within their dendrites (Cook and Werblin, 1994; Cook and McReynolds, 1998; Shields and Lukasiewicz, 2003). A17 amacrine cells supply reciprocal feedback independently of Nav channels (Chavez et al., 2006), but longer-distance signaling through the large (≥ 500 µm) (Nelson and Kolb, 1985; Raviola and Dacheux, 1987) A17 dendritic arbor could employ action potentials (Bloomfield, 1992), enabling A17s to mediate both reciprocal and lateral inhibition. To test this possibility, we measured the spatial extent of GABAergic feedback by stimulating amacrine cells directly with brief puffs of exogenous glutamate (50 µM, 25 ms) delivered in the IPL at different distances laterally from the voltage clamped RBC (Vhold = 0 mV; Chavez and Diamond, 2008). With glycinergic inhibition blocked by strychnine (3 µM) in the bath solution, this stimulation protocol elicited an outward, GABAergic IPSC in the RBC (Figure 1; Chavez, et al., 2006).

If A17s mediate both reciprocal and lateral inhibition then specific ablation of A17s by 5,7-dihydroxytryptamine (DHT), a toxic serotonin analog (Dong and Hare, 2003; Chavez et al., 2006; Grimes et al., 2009), should decrease feedback IPSCs across the entire range of distances tested. Contrary to this prediction, bath application of DHT (50 µM for 10 min) reduced glutamate-evoked feedback IPSCs only when the puff pipette was positioned directly adjacent to the synaptic terminals of the recorded RBC (to 51 ± 9% of control response at 0 µm; p = 0.01276; n = 6; Figure 1A, C) but did not significantly affect responses evoked from farther away (for 30, 50, 80 and 140 µm p-values are 0.07558, 0.15217, 0.13210, and 0.10404, respectively; Figure 1A, C). The DHT-resistant component of feedback IPSCs was abolished by subsequent application of the Nav channel blocker TTX (0.5 µM; Figure 1A, C), indicating that DHT-insensitive (non-A17) amacrine cells utilize Nav-dependent signaling to drive inhibition of RBCs (Bloomfield and Xin, 2000; Shields and Lukasiewicz, 2003; Chavez et al., 2006). These results also suggest that DHT-sensitive A17 amacrine cells make only localized reciprocal synapses onto RBC terminals. Similar results were obtained when the order of the drug application was reversed: TTX blocked feedback IPSCs evoked at distances greater than 30 µm (to 7 ± 4 of control response at 80 µm; p = 0.00007; n = 6; Fig 1B, D; p-values for 110 and 140 µm are 0.00245 and 0.00396, respectively); the local TTX-insensitive component (57 ± 6 % of control response at 0 µm) reflected GABA release from A17 cells, as it was abolished by DHT (to 3 ± 1% of TTX response; p= 0.00001; n = 6; Figure 1 B, D). Moreover, the components remaining in DHT (Figure 1C) and TTX (Figure 1D), when added together, closely approximated control responses at all puff distances (Figure 1E), indicating that the two drugs acted on independent elements contributing to GABAergic feedback. Taken together, these results indicate that, in rat retina, RBCs receive local Nav channel-independent feedback from A17 amacrine cells, and lateral, Nav channel-dependent feedback from other GABAergic amacrine cells. To isolate the lateral component of the glutamate-evoked IPSCs, all subsequent experiments were performed in the presence of DHT (50 µM).

GABACRs mediate the majority of lateral GABAergic input

GABAergic feedback IPSCs recorded from RBCs comprise both GABAA- and GABACR-mediated components (Lukasiewicz and Shields, 1998; Hartveit, 1999; Singer and Diamond, 2003; Vigh and von Gersdorff, 2005; Chavez et al., 2006; Eggers and Lukasiewicz, 2006b, a), but the relative contribution of the two receptor types at reciprocal versus lateral inputs remain unclear. Here, lateral feedback IPSCs were strongly reduced by 1,2,5,6-tetrahydropyridine-methylphosphonic acid (TPMPA; 50 µM; to 17 ± 3% of control response; n = 7, p = 0.00004; Fig 1F), a specific GABACR antagonist. The small remaining feedback IPSC was eliminated by the GABAAR antagonist, 6-imino-3-(4-methoxyphenyl)-1(6H)-pyridazinebutanoic acid hydrobromide (SR95531, 10 µM; to 1.1 ± 1.0% of control, n = 7, p = 0.00002; Figure 1F). GABABRs did not contribute because the GABAB receptor (GABABR) antagonist CGP54266 (3 µM) exerted no effect on non-reciprocal IPSCs (98 ± 2% of control IPSC, n = 4, p = 0.16; Fig 1F) (Koulen et al., 1998b). Furthermore, the complete suppression of feedback responses by ionotropic GABA receptor antagonists indicates that IPSCs were not contaminated by glutamate transporter currents (Veruki et al., 2006). Taken together, this result indicates that lateral GABAergic feedback is primarily mediated by GABACRs; this conclusion is consistent with results from light-evoked lateral inhibition recorded from RBCs in mouse (Eggers and Lukasiewicz, 2006b, a).

Presynaptic GABAergic amacrine cells express AMPA and possibly kainate receptors

Amacrine cells receive glutamatergic inputs from bipolar cells and express various subtypes of glutamate receptors (Dixon and Copenhagen, 1992; Euler et al., 1996; Dumitrescu et al., 2006). GABAergic A17 amacrine cells receive excitatory input via CP-AMPARs (Chavez et al., 2006), but glycinergic amacrine cells that contact RBCs are driven by NMDA and Ca2+-impermeable AMPARs (Chavez and Diamond, 2008). To identify which glutamate receptors are expressed by GABAergic amacrine cells providing non-reciprocal inhibition to RBCs, the effects of receptor antagonists were tested on glutamate-evoked feedback IPSCs recorded in RBCs. Glutamate-evoked IPSCs were slightly, albeit insignificantly, affected by the NMDAR antagonist 3-(2-carboxypiperazine-4-yl) propyl-1-phosphonic acid (CPP; 10 µM; to 96 ± 5 % of control, n = 11, p = 0.056; Figure 2A, D) but were reduced significantly by the specific AMPAR antagonist GYKI 53655 (GYKI, 50 µM; to 45 ± 16% of control, n = 6, p = 0.0017; Figure 2B, D) and eliminated completely by subsequent application of the AMPAR/kainate receptor (KAR) antagonist 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo (f) quinoxaline (NBQX, 25 µM; to 1 ± 1% of control, n = 6, p = 0.00044 compared to GYKI alone; Fig 2B, D). The difference in GYKI and NBQX effects suggests that both AMPARs and KARs can mediate input to GABAergic amacrine cells. Philanthotoxin 433 (PhTx, 1µM), a CP-AMPAR antagonist, also partially blocked feedback IPSCs (to 52 ± 10% of control, n = 12, p = 0.00002; Figure 2C, D). When GYKI was then added in the continued presence of PhTx, the IPSC was reduced further (to 25 ± 7% of control, n = 6, p = 0.00062, p = 0.00029 compared to PhTx alone; Fig 2C, D), leaving a small component that was eliminated by subsequent application of NBQX (25 µM; Fig 2C, D). Together these results indicate that a mixture of Ca2+ permeable and Ca2+-impermeable AMPARs primarily mediate the excitatory activation of GABAergic amacrine cells, with a small, but significant, contribution from KARs.

Figure 2
Non-NMDARs mediate excitatory inputs to lateral GABAergic amacrine cells

Lateral GABAergic feedback onto RBCs is driven mostly by the ON pathway

Exogenous agonist application (e.g., Figure 2) may activate extrasynaptic receptors that do not normally participate in synaptic transmission. To determine which glutamate receptors mediate synaptic activation of GABAergic amacrine cells, feedback IPSCs were elicited by stimulating bipolar cell dendrites in the OPL (Figure 3). ON or OFF bipolar cells were stimulated independently by puffing either the mGluR antagonist CPPG (Nawy, 2004) or the AMPAR/KAR agonist kainate (DeVries, 2000) in the OPL, respectively, ≥80 µm laterally from the RBC recording (see also Chavez and Diamond, 2008). This method stimulates synaptic circuitry in a way that is closely analogous to the light stimulation of the ON and OFF pathways (Kalbaugh et al., 2009). Both CPPG and kainate elicited feedback IPSCs in RBCs that were strongly reduced by the GABACR antagonist TPMPA (50 µM; CPPG response: to 15 ± 3% of control, n = 6, p = 0.0089; kainate response: to 9 ± 3% of control, n = 6, p = 0.0052; Figure 3A, B, G). Subsequent application of the GABAAR antagonist SR95531 (10 µM) eliminated the remainder of both the CPPG- and kainate-evoked IPSCs (CPPG response: to 3 ± 1% of control, n = 6, p = 0.00091 compared to TPMPA alone; kainate response: to 3 ± 1% of control, n = 6, p = 0.00303 compared to TPMPA alone; Figure 3A, B, G). Application of TTX (0.5 µM), which does not directly affect transmitter release from most bipolar cells (Ichinose et al., 2005; Chavez et al., 2006) but abolishes lateral feedback transmission onto RBCs (Figure 1), also eliminated both responses (CPPG: to 6 ± 6% of control, n = 7, p = 0.00001; kainate: to 6 ± 4% of control, n = 5, p = 0.00014; Figure 3C, D, G), confirming that both ON and/or OFF-responding GABAergic amacrine cells providing lateral feedback rely heavily upon Nav-dependent signaling.

Figure 3
ON and OFF retinal pathways trigger lateral inhibition from GABAergic amacrine cells

As observed with glutamate stimulation, CPPG- and kainate-evoked IPSCs were not significantly affected by the NMDAR antagonist CPP (10 µM; CPPG: to 97 ± 4% of control, n = 7, p = 0.082; kainate: to 94 ± 7% of control, n = 6, p = 0.074; Figure 3E–G), but both were strongly reduced by application of the CP-AMPAR antagonist PhTx (1µM; CPPG: to 24 ± 13% of control, n = 7, p = 0.00095; kainate: to 43 ± 12% of control, n = 6, p = 0.00024; Figure 3E–G). In both cases, the IPSC remaining in PhTx was abolished by NBQX (25 µM; CPPG: to 3 ± 3% of control, n = 7, p = 0.00645 compared to PhTx; kainate: to 4 ± 3 % of control, n = 6, p = 0.00099 compared to PhTx; Figure 3E–G). These results indicate that synaptic inputs to GABAergic amacrine cells are mediated primarily by CP-AMPARs, whereas Ca2+-impermeable AMPARs and/or KARs may be located extrasynaptically in amacrine cell membranes, as they are activated more strongly by exogenous glutamate (Figure 2) than by synaptic glutamate release from ON and OFF bipolar cells.

Although GABAergic IPSCs could be elicited by either CPPG or kainate (Figure 3), CPPG was a more effective stimulus (Figure 4). CPPG elicited IPSCs in every (24/24) cell tested, whereas kainate elicited IPSCs in only 40% (16/40) of RBCs tested (Figure 4A). Even in those cells that did respond to kainate, IPSC amplitudes (7.4 ± 1.8 pA, range 4–11 pA, n = 16) were smaller than those elicited in different cells by CPPG (10.6 ± 4.3 pA, range 4–23 pA, n = 24; p = 0.0093, unpaired t test; Figure 4A). To confirm kainate’s efficacy in a subset of non-responsive cells (n = 18), the puffer pipette was moved to the IPL, where kainate could stimulate amacrine cells directly, and robust IPSCs were detected (Figure 4B, C). Furthermore, in non-responsive cells, IPSCs were not detected even when the driving force on the GABAR chloride conductance was greatly increased (Figure 4B,C), suggesting that the lack of response was not due to RBC insensitivity. These results indicate that RBCs receive most of their non-reciprocal GABAergic inhibition from amacrine cells activated by ON bipolar cells.

Figure 4
Lateral GABAergic feedback onto RBCs is driven more strongly through the ON pathway

Multiple Ca2+ sources trigger lateral GABAergic feedback

Although calcium influx through CP-AMPARs at the A17-RBC reciprocal synapse is sufficient to trigger GABA release, it seemed unlikely that the prominent CP-AMPAR-mediated synaptic input to lateral GABAergic amacrine cells (Figure 2 and Figure 3) could do the same, because the lateral sites of excitatory input are not colocalized with the GABAergic synapses onto RBCs. Consistent with this expectation, the strong reduction of lateral feedback IPSCs by TTX (Figure 1 and Figure 3) portends a prominent role for membrane depolarization-dependent release mechanisms (i.e., Cav channels). Accordingly, bath application of cadmium (Cd2+, 200 µM), a broad-spectrum blocker of Cav channels, strongly but incompletely reduced glutamate-evoked IPSCs (to 13 ± 4 % of control response; p= 0.0020; Figure 5A, B). The remaining Cd2+-insensitive IPSC component was eliminated by PhTx (to 3 ± 2% of control, n = 6, p = 0.00228 compared to Cd2+ alone; Figure 5A, B), indicating that CP-AMPARs can contribute Ca2+-influx to trigger GABA release independently of Cav channels. Feedback IPSCs were also eliminated when Ca2+ was removed from the bath (Fig 5B), confirming that non-reciprocal GABA release is an entirely Ca2+ dependent process and that both Cav channels and Ca2+-permeable AMPARs can provide the Ca2+ influx that is required to trigger transmitter release.

Figure 5
Calcium signals underlying GABA release during lateral feedback

Most Cav channel subtypes have been shown to be expressed in the IPL (Kamphuis and Hendriksen, 1998; Xu et al., 2002), and, specifically, both N- and L- type Cav channels have been shown to mediate transmitter release from certain amacrine cells (Gleason et al., 1994; Habermann et al., 2003; Bieda and Copenhagen, 2004; Vigh and Lasater, 2004; Chavez and Diamond, 2008; Grimes et al., 2009). To explore which Cav channel subtypes contribute to non-reciprocal GABA release, Ca2+-permeable AMPARs were blocked with 1 µM PhTx and the effects of various Cav channel antagonists on glutamate-evoked IPSCs were tested. Independent application of ω-conotoxin GVIA (10 nM) or isradipine (10 µM), the N- and the L-type Cav channel antagonist, respectively, exerted large effects on feedback IPSC amplitudes (Figure 5D), but their combined application did not suppress feedback IPSCs completely (to 19 ± 5% of control, n = 5, p = 0.0013; Figure 5C, D), suggesting that other Cav channels also may play a role in triggering GABA release. Accordingly, feedback IPSCs also were reduced by T-(mibefradil, 10 µM), P/Q- (agatoxin IVA, 200 nM), and T/R-type (Ni2+, 100 µM) Cav channel antagonists (Figure 5D). Given the non-linear relationship between Ca2+ influx and transmitter release (Dodge and Rahamimoff, 1967) and the lack of highly specific Cav channel antagonists, the results presented here imply that multiple Cav channel subtypes may act cooperatively to facilitate transmitter release from amacrine cells (Bieda and Copenhagen, 2004; Chavez and Diamond, 2008).

CICR from intracellular stores contributes to Ca2+ signaling and transmitter release from amacrine cells (Gleason et al., 1994; Vigh and Lasater, 2003; Warrier et al., 2005; Chavez et al., 2006; Chavez and Diamond, 2008; Grimes et al., 2009). Here, depletion of endoplasmic reticulum (ER) Ca2+ stores with thapsigargin (1 µM) reduced lateral feedback IPSCs (to 51 ± 11% of control, n= 7, p= 0.0055; Figure 5F), indicating a role for CICR at non-reciprocal synapses. In GABAergic amacrine cells, CICR has been shown to be mediated by ryanodine receptors (RyRs) and/or inositol-1,4,5-trisphosphate receptors (IP3Rs)(Vigh and Lasater, 2003; Warrier et al., 2005; Chavez et al., 2006). When RyRs were blocked with ruthenium red (RR, 40 µM), lateral feedback IPSCs were significantly reduced (to 70 ± 8 % of control, n = 6, p=0.0056; Figure 5E, F). In contrast, when IP3Rs were blocked with either 2-APB (50 µM) or Xestospongin C (XeC, 3 µM), IPSCs were unaffected (2-APB: to 94 ± 5 % of control, n = 6, p = 0.050; XeC: to 93 ± 9 % of control, n = 4, p = 0.27; Figure 5F), suggesting that RyRs but not IP3Rs trigger CICR to amplify intracellular Ca2+ signals at non-reciprocal synapses and enhance GABA release. Consistent with this conclusion, puff application of the RyR agonist caffeine (15 mM) evoked IPSCs that were eliminated by GABAR antagonists (to 2 ± 1 % of control, n = 4, p= 0.016; Figure 5F) or strongly reduced by RR (to 13 ± 4 % of control, n = 5, p = 0.00009; Figure 5F). Taken together, these results indicate that Cav channels, CP-AMPARs and RyR mediated CICR contribute to intracellular Ca2+ signals that trigger GABA release at lateral feedback synapses onto RBCs.

GABAR activation at reciprocal and lateral feedback synapses

Lateral GABAergic feedback inhibition onto RBC terminals is mediated mostly by GABACRs (Figure 1F, Figure 3A, 3B). Reciprocal feedback elicited by depolarization of a single RBC activates primarily GABAARs (Chavez et al., 2006), but when release from A17s is enhanced a GABACR-mediated component emerges in the reciprocal feedback IPSC (Hartveit, 1999; Singer and Diamond, 2003; Vigh and von Gersdorff, 2005; Chavez et al., 2006). GABAARs and GABACRs are clustered separately on RBC axon terminals (Koulen et al., 1998a) and typically only GABAARs are activated by spontaneous GABA release (Frech and Backus, 2004; Eggers and Lukasiewicz, 2006b; Palmer, 2006), suggesting that the two receptor types may localized to different synapses. One possibility – that GABACRs are localized to lateral synapses but can be activated by GABA spillover from reciprocal synapses – is countered by anatomical evidence that GABACRs are expressed at RBC-A17 contacts (Fletcher et al., 1998). Alternatively, GABACRs may be located perisynaptically at either synapse type and become activated only during enhanced release by GABA spillover (Ichinose and Lukasiewicz, 2002; Vigh and von Gersdorff, 2005; Eggers and Lukasiewicz, 2006a; Hull et al., 2006). It is also possible that both receptor types are localized separately at different reciprocal and lateral synapses but that GABACRs, which bind transmitter much more slowly (Chang and Weiss, 1999), are activated only in response to evoked release of multiple GABA vesicles (Supplementary Figure 1).

To explore these possibilities, we first re-examined the contribution of GABACRs to reciprocal feedback. In the presence of TTX (0.5 µM) and in the absence of DHT, we evoked reciprocal feedback IPSCs by depolarizing a single RBC from −60 to −10 mV. Under these conditions, reciprocal IPSCs are mediated primarily by GABAARs (Singer and Diamond, 2003; Chavez et al., 2006; Chavez and Diamond, 2008) and exhibited characteristically rapid kinetics (Fig 6A). As shown previously (Singer and Diamond, 2003), blocking AMPAR desensitization with cyclothiazide (CTZ, 50 µM) increased reciprocal GABA release and caused a slower, GABACR-mediated component to emerge in the reciprocal IPSC (Figure 6A). Although CTZ has been reported to antagonize both GABAAR and GABACRs (Deng and Chen, 2003; Xie et al., 2008), in our hands CTZ reduced only slightly GABAAR activation and exerted no effect on GABACR activation in response to exogenous GABA puffs (Supplementary Figure 2A–D). We also observed that CTZ potentiated GABA release from A17 amacrine cells when stimulated by exogenous glutamate puffs (to 173 ± 17 % of control response; p = 0.00137; Supplementary Figure 2; Grimes et al 2009). Application of a GABAAR antagonist (SR95531, 10 µM) in the continued presence of CTZ significantly reduced the fast, transient component of the step-evoked feedback response but did not affect the slow, prolonged component (Figure 6A). Further inclusion of TPMPA (50 µM) abolished this slow component (to 2 ± 1% of CTZ current; p = 0.00018; n = 8; Figure 6A), confirming that it was mediated by GABACRs (Singer and Diamond, 2003; Vigh and von Gersdorff, 2005).

If, during enhanced reciprocal GABA release, GABACR activation were exclusively extrasynaptic (Vigh and von Gersdorff, 2005), one might expect that blocking GABA transporters, thereby slowing GABA clearance, would enhance activation of extrasynaptic GABACRs. To test this idea, step-evoked IPSCs were recorded in the presence of CTZ (50 µM; Figure 6B), and then GABA transporters (GAT-1) were blocked by NO-711 (10 µM). Consistent with previous results, NO-711 applied alone (Chavez et al., 2006; Eggers and Lukasiewicz, 2006a) or in presence of CTZ did not substantially increase GABAAR-mediated step-evoked IPSCs (to 101 ± 4 % of CTZ response; p=0.70741; n=6; Figure 6B). Similarly, NO-711 only slightly but insignificantly increased the slow GABACR-mediated step-evoked IPSC (to 112 ± 14 % of CTZ response; n=5; p=0.06071; Figure 6B), suggesting that GAT-1 does not strongly regulate GABAergic transmission at reciprocal synapses. It is unlikely that GABA transporters were saturated under these conditions, because GABA transporters limit the activation of GABACRs even when the entire network is activated simultaneously by full field light stimulation (Eggers and Lukasiewicz, 2006a). Although this result does not exclude spillover between reciprocal and lateral synapses, it suggests that such spillover is not regulated by GAT-1.

If GABACR activation by GABA spillover mediated significant interaction between reciprocal and lateral synapses, coincident activation of both two pathways could elicit a response that was smaller than the sum of the individual components. This prediction was tested in the presence of 50 µM CTZ and 10 µM SR95531, with TTX removed from the ASCF to allow for activation of both reciprocal and non-reciprocal inputs. Lateral synaptic inputs were stimulated with glutamate puffs ~60–80 µM away from the recorded RBC (Figure 6C), and reciprocal inputs were elicited by step depolarization of the RBC (from −60 to −10 mV for 1 or 3 sec; Figure 6D). Lateral IPSCs were evoked before (black trace, Figure 6C), during (arrow in Fig 6D), or after the depolarizing voltage-step (red trace, Figure 6C). In all cells tested (n =10; Fig 6E, F), neither the amplitude nor the kinetics of lateral GABACR-mediated IPSCs were affected by coincident activation of reciprocal feedback (Figure 6D–F), suggesting that the two forms of feedback activated distinct pools of GABACRs.

Discussion

The present study identifies the cellular and synaptic mechanisms underlying lateral GABAergic feedback onto rat RBC axon terminals and makes comparisons to reciprocal feedback mediated by A17 amacrine cells. Although this electrophysiological study does not directly identify the GABAergic amacrine cell subtypes that mediate non-reciprocal inhibitory inputs, it does provide evidence that distinct sets of amacrine cells mediate reciprocal and lateral GABAergic feedback, highlighting the diversity of physiological mechanisms that underlie inhibitory transmitter release onto RBCs. Specializations among GABAergic amacrine cells might reflect a necessary means to suppress distinct spatial or temporal components of visual signaling in the rod pathway. For example, responses at lateral feedback synapses are largely GABACR-mediated (Figure 1Figure 3), suggesting that these inhibitory inputs could be important in shaping tonic glutamate release from RBCs by suppressing regenerative potentials at RBC terminals (Ichinose and Lukasiewicz, 2002; Hull et al., 2006). In contrast, local reciprocal synapses, due to their fast activation kinetics, may play a modulatory role in conferring transience to the visual signal (Euler and Masland, 2000; Dong and Hare, 2003) and/or preventing the rapid depletion of the readily-releasable vesicle pool in RBC terminals (Singer and Diamond, 2006). It remains to be determined, however, whether these distinct GABA feedback pathways independently modulate RBC outputs during light evoked signaling.

In addition to contacting bipolar cell terminals and ganglion cell dendrites, amacrine cells also contact other amacrine cells (Dowling and Boycott, 1966; Dowling and Werblin, 1969; Zhang et al., 2004), primarily via GABAAR-mediated synapses (Zhang et al., 1997; Fletcher et al., 1998; Wassle et al., 1998; Eggers and Lukasiewicz, 2009). Although such “serial inhibition” (Zhang et al., 1997) was not evident in our recordings, we cannot exclude the possibility that amacrine-amacrine signaling may have influenced the results of some pharmacological manipulations.

Distinct cell types mediate local vs. lateral GABAergic inhibition

Although some GABAergic amacrine cells can mediate both local and lateral signaling (Cook and McReynolds, 1998) and surround receptive-field organization to ganglion cells (Ichinose and Lukasiewicz, 2005), GABAergic amacrine cells that mediate reciprocal or lateral inhibition to RBCs utilize unique physiological mechanisms and comprise distinct cell types. At reciprocal synapses, GABA release can occur in the absence of Cav channel activation, triggered instead by Ca2+ influx through glutamate receptors (Chavez et al., 2006). Co-localization of excitatory and inhibitory synapses at individual varicosities (Ellias and Stevens, 1980; Nelson and Kolb, 1985) suggests that each A17 reciprocal synapse may operate independently. Consistent with this idea, puff-evoked feedback inhibition from A17 amacrine cells was highly localized to within ~30 µm of the inhibited RBC (Figure 1). In contrast to local reciprocal inhibition from A17, lateral feedback likely plays an important role in spatial processing and thus requires Nav channel activation to boost the propagation of membrane depolarization throughout the dendritic arbor. This type of global response/depolarization leads to the activation of Cav channels, predominantly the L- and N- subtypes, that trigger the release of GABA (Figure 5). Although Cav channels could be activated by the passive, electrotonic spread of depolarization, the strong sensitivity to TTX (Fig 1, ,3)3) suggests that the dendritic trees of “lateral” GABAergic amacrine cells possess active conductances that may allow them to generate action potentials (Miller and Dacheux, 1976; Masland, 1988; Bloomfield, 1992; Heflin and Cook, 2007).

Synaptic AMPARs but not NMDARs mediate inputs to GABAergic amacrine cells

Some amacrine cells express NMDARs (Dixon and Copenhagen, 1992; Boos et al., 1993; Hartveit and Veruki, 1997; Dumitrescu et al., 2006; Chavez and Diamond, 2008), but the range of NMDAR-positive cell types is unknown. Here we find that NMDARs do not contribute to the activation of GABAergic amacrine cells providing lateral feedback to RBCs, similar to previous results at reciprocal GABAergic synapses (Hartveit, 1999; Singer and Diamond, 2003; Chavez et al., 2006). Our pharmacological results suggest possible colocalization of Ca2+-permeable and Ca2+-impermeable AMPAR subtypes on non-reciprocal amacrine cells (Figure 2, ,3),3), as observed in other retinal neurons (Zhang et al., 1995; Huang and Liang, 2005). Although more thorough examination of glutamate receptor expression by specific amacrine cell subtypes is clearly required, the present results, together with previous physiological work, suggests that GABAergic amacrine cells in the rod pathway express primarily AMPARs (Hartveit, 1999; Singer and Diamond, 2003), while glycinergic amacrine cells also express NMDARs (Hartveit and Veruki, 1997; Chavez and Diamond, 2008). The functional consequences of such specificity, which may not extend to all amacrine cell types (Dumitrescu et al., 2006), remains to be determined.

Ca2+ signals underlying non-reciprocal GABA transmitter release

Typically, presynaptic Ca2+ influx required to trigger transmitter release involves activation of Cav channels (Katz and Miledi, 1967) but in some GABAergic interneurons, Ca2+ influx mediated by NMDARs (Schoppa et al., 1998; Isaacson, 2001; Vigh and von Gersdorff, 2005) or Ca2+-permeable AMPARs (Chavez et al., 2006) can trigger transmitter release. Co-localization of excitatory receptors and GABA release machinery would be expected for this phenomena to occur, but we find that activation of Ca2+-permeable AMPARs on non-reciprocal GABAergic amacrine cells can trigger some GABA release (Figure 5), although N- and L- type Cav channels provide the majority of Ca2+ that drives release (Figure 5). Previous reports indicate that L-type channels often underlie calcium signals and transmitter release at tonically releasing ribbon synapses (Sterling and Matthews, 2005), whereas N-type channels mediate phasic transmitter release at other synapses (Reid et al., 2003). Having multiple CaV channel types control non-reciprocal GABA release may enable specific regulation of synaptic signaling and likely reflects the functional diversity of amacrine cells.

Previous evidence indicates that CICR boosts inhibitory synaptic transmission from amacrine cells (Gleason et al., 1994; Vigh and Lasater, 2003; Warrier et al., 2005; Chavez et al., 2006; Chavez and Diamond, 2008). In “lateral” GABAergic amacrine cells, the enhancement of GABA release onto RBC terminals by CICR is triggered primarily by activation of RyRs but not IP3Rs (Figure 5), analogous to our previous results in A17 amacrine cells (Chavez et al., 2006). The two CICR pathways appear to be segregated to different forms of inhibition: in some amacrine cells, IP3Rs, but not RyRs, are activated by Ca2+ influx through NMDARs (Chavez and Diamond, 2008) and/or intracellular signals from metabotropic glutamate receptors (Warrier et al., 2005; Chavez and Diamond, 2008).

RBCs receive GABAergic feedback inhibition from both ON and OFF pathways

The dendritic arbors of wide-field GABAergic amacrine cells extend over great lengths laterally but are typically confined within narrow strata in the IPL and are therefore likely restricted to either the ON or OFF sublaminae (Masland, 1988; MacNeil and Masland, 1998). Here we find that lateral GABAergic inputs to RBCs are driven through both the ON and the OFF pathways (Figure 3). Notably, however, feedback inputs to RBCs driven by the OFF pathway are smaller in size and less frequently observed than those supplied by the ON pathway (Figure 4). Although it is possible that these GABAergic inputs to RBCs are mediated by amacrine cells that are activated purely by ON or OFF channels, combinations of ON and OFF inputs cannot be ruled out (Werblin and Dowling, 1969; Dacheux and Raviola, 1995; Bloomfield and Volgyi, 2007). Previous work on amacrine cells that respond to both light increments and decrements has shown that these cells can mediate feedforward inhibition to ganglion cells (Cook and Werblin, 1994; Taylor, 1999) or feedback inhibition onto bipolar cells (Shields and Lukasiewicz, 2003) and possess a similar sensitivity to TTX (Miller and Dacheux, 1976; Werblin, 1977; Cook and Werblin, 1994; Miller et al., 2006; Bloomfield and Volgyi, 2007), as observed here (Figure 3).

GABACR are located at both reciprocal and non-reciprocal synaptic inputs

The apparent segregation of GABAARs and GABACRs at the axon terminals of RBCs (Fletcher et al., 1998; Koulen et al., 1998a; Palmer, 2006) is a matter of debate. Previous evidence indicates that GABAARs mediate most of the reciprocal synaptic inputs (Singer and Diamond, 2003; Chavez et al., 2006), but during increased reciprocal GABA release, GABACRs can also be recruited (Hartveit, 1999; Singer and Diamond, 2003; Vigh and von Gersdorff, 2005; Chavez et al., 2006; Eggers and Lukasiewicz, 2006a, b). Here we find that, although GABA release from non-reciprocal GABAergic amacrine cells activates both GABAARs and GABACRs (Figure 1, ,3),3), the majority of the non-reciprocal GABA response (≥ 90%) is mediated by GABACRs. One interpretation is that distinct GABACR populations may be responsible for signaling at reciprocal versus non-reciprocal inputs (Palmer, 2006), but it is also possible that these receptors could be located extrasynaptically (Vigh and von Gersdorff, 2005) and shared by the two types of synapses. Consistent with the former possibilities, we find that the activation GABACRs during non-reciprocal GABAergic feedback does not occlude activation of GABACRs during enhanced reciprocal feedback (Figure 6), suggesting that the responding GABACRs comprise distinct, non-overlapping populations and thus preserving the range of lateral and reciprocal inhibition to RBCs.

Supplementary Material

Supp1

Acknowledgements

We thank members of the Diamond lab for constructive discussions throughout the project. This research was supported by the NINDS Intramural Research Program.

References

  • Bieda MC, Copenhagen DR. N-type and L-type calcium channels mediate glycinergic synaptic inputs to retinal ganglion cells of tiger salamanders. Vis Neurosci. 2004;21:545–550. [PMC free article] [PubMed]
  • Bloomfield SA. Relationship between receptive and dendritic field size of amacrine cells in the rabbit retina. J Neurophysiol. 1992;68:711–725. [PubMed]
  • Bloomfield SA, Xin D. Surround inhibition of mammalian AII amacrine cells is generated in the proximal retina. J Physiol. 2000;523(Pt 3):771–783. [PMC free article] [PubMed]
  • Bloomfield SA, Volgyi B. Response properties of a unique subtype of wide-field amacrine cell in the rabbit retina. Vis Neurosci. 2007;24:459–469. [PubMed]
  • Boos R, Schneider H, Wassle H. Voltage- and transmitter-gated currents of all-amacrine cells in a slice preparation of the rat retina. J Neurosci. 1993;13:2874–2888. [PubMed]
  • Chang Y, Weiss DS. Channel opening locks agonist onto the GABAC receptor. Nat Neurosci. 1999;2:219–225. [PubMed]
  • Chavez AE, Diamond JS. Diverse mechanisms underlie glycinergic feedback transmission onto rod bipolar cells in rat retina. J Neurosci. 2008;28:7919–7928. [PMC free article] [PubMed]
  • Chavez AE, Singer JH, Diamond JS. Fast neurotransmitter release triggered by Ca influx through AMPA-type glutamate receptors. Nature. 2006;443:705–708. [PubMed]
  • Cook PB, Werblin FS. Spike initiation and propagation in wide field transient amacrine cells of the salamander retina. J Neurosci. 1994;14:3852–3861. [PubMed]
  • Cook PB, McReynolds JS. Lateral inhibition in the inner retina is important for spatial tuning of ganglion cells. Nat Neurosci. 1998;1:714–719. [PubMed]
  • Cui J, Ma YP, Lipton SA, Pan ZH. Glycine receptors and glycinergic synaptic input at the axon terminals of mammalian retinal rod bipolar cells. J Physiol. 2003;553:895–909. [PMC free article] [PubMed]
  • Dacheux RF, Raviola E. Light responses from one type of ON-OFF amacrine cells in the rabbit retina. J Neurophysiol. 1995;74:2460–2468. [PubMed]
  • Deng L, Chen G. Cyclothiazide potently inhibits gamma-aminobutyric acid type A receptors in addition to enhancing glutamate responses. Proc Natl Acad Sci U S A. 2003;100:13025–13029. [PMC free article] [PubMed]
  • DeVries SH. Bipolar cells use kainate and AMPA receptors to filter visual information into separate channels. Neuron. 2000;28:847–856. [PubMed]
  • Dixon DB, Copenhagen DR. Two types of glutamate receptors differentially excite amacrine cells in the tiger salamander retina. J Physiol. 1992;449:589–606. [PMC free article] [PubMed]
  • Dodge FA, Jr., Rahamimoff R. Co-operative action a calcium ions in transmitter release at the neuromuscular junction. J Physiol. 1967;193:419–432. [PMC free article] [PubMed]
  • Dong CJ, Hare WA. Temporal modulation of scotopic visual signals by A17 amacrine cells in mammalian retina in vivo. J Neurophysiol. 2003;89:2159–2166. [PubMed]
  • Dowling JE, Boycott BB. Organization of the primate retina: electron microscopy. Proc R Soc Lond B Biol Sci. 1966;166:80–111. [PubMed]
  • Dowling JE, Werblin FS. Organization of retina of the mudpuppy, Necturus maculosus. I. Synaptic structure. J Neurophysiol. 1969;32:315–338. [PubMed]
  • Dumitrescu ON, Protti DA, Majumdar S, Zeilhofer HU, Wassle H. Ionotropic glutamate receptors of amacrine cells of the mouse retina. Vis Neurosci. 2006;23:79–90. [PubMed]
  • Eggers ED, Lukasiewicz PD. Receptor and transmitter release properties set the time course of retinal inhibition. J Neurosci. 2006a;26:9413–9425. [PubMed]
  • Eggers ED, Lukasiewicz PD. GABA(A), GABA(C) and glycine receptor-mediated inhibition differentially affects light-evoked signalling from mouse retinal rod bipolar cells. J Physiol. 2006b;572:215–225. [PMC free article] [PubMed]
  • Eggers ED, Lukasiewicz PD. Interneuron circuits tune inhibition in retinal bipolar cells. J Neurophysiol. 2009 Nov 11; Epub ahead of print. [PMC free article] [PubMed]
  • Eggers ED, McCall MA, Lukasiewicz PD. Presynaptic inhibition differentially shapes transmission in distinct circuits in the mouse retina. J Physiol. 2007;582:569–582. [PMC free article] [PubMed]
  • Ellias SA, Stevens JK. The dendritic varicosity: a mechanism for electrically isolating the dendrites of cat retinal amacrine cells? Brain Res. 1980;196:365–372. [PubMed]
  • Euler T, Masland RH. Light-evoked responses of bipolar cells in a mammalian retina. J Neurophysiol. 2000;83:1817–1829. [PubMed]
  • Euler T, Schneider H, Wassle H. Glutamate responses of bipolar cells in a slice preparation of the rat retina. J Neurosci. 1996;16:2934–2944. [PubMed]
  • Fletcher EL, Koulen P, Wassle H. GABAA and GABAC receptors on mammalian rod bipolar cells. J Comp Neurol. 1998;396:351–365. [PubMed]
  • Frech MJ, Backus KH. Characterization of inhibitory postsynaptic currents in rod bipolar cells of the mouse retina. Vis Neurosci. 2004;21:645–652. [PubMed]
  • Gleason E, Borges S, Wilson M. Control of transmitter release from retinal amacrine cells by Ca2+ influx and efflux. Neuron. 1994;13:1109–1117. [PubMed]
  • Grimes WN, Li W, Chavez AE, Diamond JS. BK channels modulate pre- and postsynaptic signaling at reciprocal synapses in retina. Nat Neurosci. 2009;12:585–592. [PMC free article] [PubMed]
  • Grunert U, Martin PR. Rod bipolar cells in the macaque monkey retina: immunoreactivity and connectivity. J Neurosci. 1991;11:2742–2758. [PubMed]
  • Habermann CJ, O'Brien BJ, Wassle H, Protti DA. AII amacrine cells express L-type calcium channels at their output synapses. J Neurosci. 2003;23:6904–6913. [PubMed]
  • Hartveit E. Reciprocal synaptic interactions between rod bipolar cells and amacrine cells in the rat retina. J Neurophysiol. 1999;81:2923–2936. [PubMed]
  • Hartveit E, Veruki ML. AII amacrine cells express functional NMDA receptors. Neuroreport. 1997;8:1219–1223. [PubMed]
  • Heflin SJ, Cook PB. Narrow and wide field amacrine cells fire action potentials in response to depolarization and light stimulation. Vis Neurosci. 2007;24:197–206. [PubMed]
  • Huang SY, Liang PJ. Ca2+-permeable and Ca2+-impermeable AMPA receptors coexist on horizontal cells. Neuroreport. 2005;16:263–266. [PubMed]
  • Hull C, Li GL, von Gersdorff H. GABA transporters regulate a standing GABAC receptor-mediated current at a retinal presynaptic terminal. J Neurosci. 2006;26:6979–6984. [PMC free article] [PubMed]
  • Ichinose T, Lukasiewicz PD. GABA transporters regulate inhibition in the retina by limiting GABA(C) receptor activation. J Neurosci. 2002;22:3285–3292. [PubMed]
  • Ichinose T, Lukasiewicz PD. Inner and outer retinal pathways both contribute to surround inhibition of salamander ganglion cells. J Physiol. 2005;565:517–535. [PMC free article] [PubMed]
  • Ichinose T, Shields CR, Lukasiewicz PD. Sodium channels in transient retinal bipolar cells enhance visual responses in ganglion cells. J Neurosci. 2005;25:1856–1865. [PubMed]
  • Isaacson JS. Mechanisms governing dendritic gamma-aminobutyric acid (GABA) release in the rat olfactory bulb. Proc Natl Acad Sci U S A. 2001;98:337–342. [PMC free article] [PubMed]
  • Ivanova E, Muller U, Wassle H. Characterization of the glycinergic input to bipolar cells of the mouse retina. Eur J Neurosci. 2006;23:350–364. [PubMed]
  • Kalbaugh TL, Zhang J, Diamond JS. Coagonist release modulates NMDA receptor subtype contributions at synaptic inputs to retinal ganglion cells. J Neurosci. 2009;29:1469–1479. [PMC free article] [PubMed]
  • Kamphuis W, Hendriksen H. Expression patterns of voltage-dependent calcium channel alpha 1 subunits (alpha 1A-alpha 1E) mRNA in rat retina. Brain Res Mol Brain Res. 1998;55:209–220. [PubMed]
  • Katz B, Miledi R. Ionic requirements of synaptic transmitter release. Nature. 1967;215:651. [PubMed]
  • Kolb H, Nelson R. Amacrine cells of the cat retina. Vision Res. 1981;21:1625–1633. [PubMed]
  • Koulen P, Brandstatter JH, Enz R, Bormann J, Wassle H. Synaptic clustering of GABA(C) receptor rho-subunits in the rat retina. Eur J Neurosci. 1998a;10:115–127. [PubMed]
  • Koulen P, Malitschek B, Kuhn R, Bettler B, Wassle H, Brandstatter JH. Presynaptic and postsynaptic localization of GABA(B) receptors in neurons of the rat retina. Eur J Neurosci. 1998b;10:1446–1456. [PubMed]
  • Lavoie AM, Tingey JJ, Harrison NL, Pritchett DB, Twyman RE. Activation and deactivation rates of recombinant GABA(A) receptor channels are dependent on alpha-subunit isoform. Biophys J. 1997;73:2518–2526. [PMC free article] [PubMed]
  • Lukasiewicz PD, Shields CR. A diversity of GABA receptors in the retina. Semin Cell Dev Biol. 1998;9:293–299. [PubMed]
  • MacNeil MA, Masland RH. Extreme diversity among amacrine cells: implications for function. Neuron. 1998;20:971–982. [PubMed]
  • Masland RH. Amacrine cells. Trends Neurosci. 1988;11:405–410. [PubMed]
  • Miller RF, Dacheux R. Dendritic and somatic spikes in mudpuppy amacrine cells: indentification and TTX sensitivity. Brain Res. 1976;104:157–162. [PubMed]
  • Miller RF, Staff NP, Velte TJ. Form and function of ON-OFF amacrine cells in the amphibian retina. J Neurophysiol. 2006;95:3171–3190. [PubMed]
  • Nawy S. Desensitization of the mGluR6 transduction current in tiger salamander On bipolar cells. J Physiol. 2004;558:137–146. [PMC free article] [PubMed]
  • Nelson R, Kolb H. A17: a broad-field amacrine cell in the rod system of the cat retina. J Neurophysiol. 1985;54:592–614. [PubMed]
  • Palmer MJ. Functional segregation of synaptic GABAA and GABAC receptors in goldfish bipolar cell terminals. J Physiol. 2006;577:45–53. [PMC free article] [PubMed]
  • Raviola E, Dacheux RF. Excitatory dyad synapse in rabbit retina. Proc Natl Acad Sci U S A. 1987;84:7324–7328. [PMC free article] [PubMed]
  • Reid CA, Bekkers JM, Clements JD. Presynaptic Ca2+ channels: a functional patchwork. Trends Neurosci. 2003;26:683–687. [PubMed]
  • Schoppa NE, Kinzie JM, Sahara Y, Segerson TP, Westbrook GL. Dendrodendritic inhibition in the olfactory bulb is driven by NMDA receptors. J Neurosci. 1998;18:6790–6802. [PubMed]
  • Shields CR, Lukasiewicz PD. Spike-dependent GABA inputs to bipolar cell axon terminals contribute to lateral inhibition of retinal ganglion cells. J Neurophysiol. 2003;89:2449–2458. [PubMed]
  • Singer JH, Diamond JS. Sustained Ca2+ entry elicits transient postsynaptic currents at a retinal ribbon synapse. J Neurosci. 2003;23:10923–10933. [PubMed]
  • Singer JH, Diamond JS. Vesicle depletion and synaptic depression at a mammalian ribbon synapse. J Neurophysiol. 2006;95:3191–3198. [PubMed]
  • Sterling P, Lampson LA. Molecular specificity of defined types of amacrine synapse in cat retina. J Neurosci. 1986;6:1314–1324. [PubMed]
  • Sterling P, Matthews G. Structure and function of ribbon synapses. Trends Neurosci. 2005;28:20–29. [PubMed]
  • Taylor WR. TTX attenuates surround inhibition in rabbit retinal ganglion cells. Vis Neurosci. 1999;16:285–290. [PubMed]
  • Veruki ML, Morkve SH, Hartveit E. Activation of a presynaptic glutamate transporter regulates synaptic transmission through electrical signaling. Nat Neurosci. 2006;9:1388–1396. [PubMed]
  • Vigh J, Lasater EM. Intracellular calcium release resulting from mGluR1 receptor activation modulates GABAA currents in wide-field retinal amacrine cells: a study with caffeine. Eur J Neurosci. 2003;17:2237–2248. [PubMed]
  • Vigh J, Lasater EM. L-type calcium channels mediate transmitter release in isolated, wide-field retinal amacrine cells. Vis Neurosci. 2004;21:129–134. [PubMed]
  • Vigh J, von Gersdorff H. Prolonged reciprocal signaling via NMDA and GABA receptors at a retinal ribbon synapse. J Neurosci. 2005;25:11412–11423. [PubMed]
  • Volgyi B, Xin D, Bloomfield SA. Feedback inhibition in the inner plexiform layer underlies the surround-mediated responses of AII amacrine cells in the mammalian retina. J Physiol. 2002;539:603–614. [PMC free article] [PubMed]
  • Warrier A, Borges S, Dalcino D, Walters C, Wilson M. Calcium from internal stores triggers GABA release from retinal amacrine cells. J Neurophysiol. 2005;94:4196–4208. [PubMed]
  • Wassle H, Koulen P, Brandstatter JH, Fletcher EL, Becker CM. Glycine and GABA receptors in the mammalian retina. Vision Res. 1998;38:1411–1430. [PubMed]
  • Werblin FS. Regenerative amacrine cell depolarization and formation of on-off ganglion cell response. J Physiol. 1977;264:767–785. [PMC free article] [PubMed]
  • Werblin FS, Dowling JE. Organization of the retina of the mudpuppy, Necturus maculosus. II. Intracellular recording. J Neurophysiol. 1969;32:339–355. [PubMed]
  • Xie A, Song X, Ripps H, Qian H. Cyclothiazide: a subunit-specific inhibitor of GABAC receptors. J Physiol. 2008;586:2743–2752. [PMC free article] [PubMed]
  • Xu HP, Zhao JW, Yang XL. Expression of voltage-dependent calcium channel subunits in the rat retina. Neurosci Lett. 2002;329:297–300. [PubMed]
  • Zhang D, Sucher NJ, Lipton SA. Co-expression of AMPA/kainate receptor-operated channels with high and low Ca2+ permeability in single rat retinal ganglion cells. Neuroscience. 1995;67:177–188. [PubMed]
  • Zhang J, Jung CS, Slaughter MM. Serial inhibitory synapses in retina. Vis Neurosci. 1997;14:553–563. [PubMed]
  • Zhang J, Wang HH, Yang CY. Synaptic organization of GABAergic amacrine cells in the salamander retina. Vis Neurosci. 2004;21:817–825. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...