Chavez, A.E., Singer, J.H. & Diamond, J.S. Fast neurotransmitter release triggered by Ca influx through AMPA-type glutamate receptors. Nature 443, 705-708

Synaptic Physiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3701, USA.
Nature (Impact Factor: 41.46). 11/2006; 443(7112):705-8. DOI: 10.1038/nature05123
Source: PubMed


Feedback inhibition at reciprocal synapses between A17 amacrine cells and rod bipolar cells (RBCs) shapes light-evoked responses in the retina. Glutamate-mediated excitation of A17 cells elicits GABA (gamma-aminobutyric acid)-mediated inhibitory feedback onto RBCs, but the mechanisms that underlie GABA release from the dendrites of A17 cells are unknown. If, as observed at all other synapses studied, voltage-gated calcium channels (VGCCs) couple membrane depolarization to neurotransmitter release, feedforward excitatory postsynaptic potentials could spread through A17 dendrites to elicit 'surround' feedback inhibitory transmission at neighbouring synapses. Here we show, however, that GABA release from A17 cells in the rat retina does not depend on VGCCs or membrane depolarization. Instead, calcium-permeable AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs), activated by glutamate released from RBCs, provide the calcium influx necessary to trigger GABA release from A17 cells. The AMPAR-mediated calcium signal is amplified by calcium-induced calcium release (CICR) from intracellular calcium stores. These results describe a fast synapse that operates independently of VGCCs and membrane depolarization and reveal a previously unknown form of feedback inhibition within a neural circuit.

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    • "The GCL contains RGCs and displaced amacrine cells (Schmidt et al., 1985; Perez De Sevilla Müller et al., 2007), while the INL is composed of three types of interneurons: bipolar, horizontal and amacrine cells. Both bipolar and amacrine cells synapse onto ganglion cells and transmit light responses from rod and cone photoreceptor cells (Kolb, 1997; Chávez et al., 2006; Dumitrescu et al., 2009; Masland, 2011; Asari and Meister, 2012). In the INL, RdgB2 immunostaining appeared to be restricted to amacrine cells since the staining was exclusively in the proximal region of the INL directly adjacent to the IPL (Figure 1, A and B), and bipolar and horizontal cells are found only more distally in the INL. "
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    ABSTRACT: A subset of retinal ganglion cells is intrinsically photosensitive (ipRGCs), and contributes directly to the pupillary light reflex and circadian photoentrainment under bright light conditions. ipRGCs are also indirectly activated by light through cellular circuits initiated in rods and cones. A mammalian homolog (RdgB2) of a phosphoinositide transfer/exchange protein that functions in Drosophila phototransduction is expressed in the retinal ganglion cell layer. This raised the possibility that RdgB2 might function in the intrinsic light response in ipRGCs, which depends on a cascade reminiscent of Drosophila phototransduction. Here, we found that under high light intensities RdgB2(-/-) mutant mice showed normal pupillary light responses and circadian photoentrainment. Consistent with this behavioral phenotype, the intrinsic light responses of ipRGCs in RdgB2(-/-) were indistinguishable from wild-type. In contrast, under low light conditions, RdgB2(-/-) mutants displayed defects in both circadian photoentrainment and the pupillary light response. The RdgB2 protein was not expressed in ipRGCs, but in GABAergic amacrine cells, which provided inhibitory feedback onto bipolar cells. We propose that RdgB2 is required in a cellular circuit that transduces light input from rods to bipolar cells that are coupled to GABAergic amacrine cells and ultimately to ipRGCs, thereby enabling ipRGCs to respond to dim light.
    Full-text · Article · Aug 2015 · Molecular biology of the cell
    • "In the inner retina, GABAergic and glycinergic amacrine cells interact with the axon terminals of rodent rod bipolar cells (Hartveit, 1996, 1999; Ch avez et al., 2006; Ch avez et al., 2010). A17 amacrine cells generate reciprocal inhibition via GABA type A receptors (GABA A Rs) (Ch avez et al., 2006), whereas an unknown amacrine cell type generates lateral inhibition that depends on Na v and operates predominately through GABA C Rs (Ch avez et al., 2006; Ch avez et al., 2010; Castilho et al., 2015; Moore-Dotson et al., 2015). In addition, serial inhibition between amacrine cells suppresses GABA C input to rod bipolar cells via GABA A R activation (Eggers & Lukasiewicz, 2010a,b). "
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    ABSTRACT: Reducing signal gain in the highly sensitive rod pathway prevents saturation as background light levels increase, allowing the dark-adapted retina to encode stimuli over a range of background luminances. Dopamine release is increased during light adaptation and is generally accepted to suppress rod signaling in light-adapted retinas. However, recent research has suggested that dopamine, acting through D1 receptors, could additionally produce a sensitization of the rod pathway in dim light conditions via GABAc receptors. Here, we evaluate the overall activity of the depolarizing bipolar cell population (DBCs) in vivo to ensure the integrity of long-distance network interactions by quantifying the b-wave of the electroretinogram. We show that dopamine, acting through D1 receptors, reduces the amplitude and sensitivity of rod-driven DBCs during light adaptation by suppressing GABAA R-mediated serial inhibition onto rod DBC GABAC Rs. Block of D1 receptors does not suppress rod-driven DBC sensitivity when GABAA -mediated serial inhibition is blocked by gabazine, suggesting that the reduction in rod-driven DBC sensitivity in the absence of D1 receptors is due to disinhibition of serial inhibitory GABAergic circuitry rather than a direct facilitatory effect on GABA release onto rod-driven DBC GABAC receptors. Finally, the large population of GABAergic A17 wide-field amacrine cells known to maintain reciprocal inhibition with rod DBCs could be excluded from the proposed disinhibitory circuit after treatment with 5,7- dihydroxytryptamine. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · European Journal of Neuroscience
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    • "In 3D space, proximal synapses were located, on average, 220 130 nm (mean SD, median 165 nm) from the excitatory input synapse, whereas the distal synapse was located, on average, more than twice that distance (510 150 nm; median 490 nm; Fig. 1G). Previous experiments showed that Ca 2 influx through postsynaptic AMPARs can trigger vesicular GABA release from A17s (Chavez et al. 2006). At most synapses, vesicle release machinery and Ca 2 channels are tightly colocalized within the presynaptic active zone (Issa and Hudspeth 1994; Jarsky et al. 2010). "
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    ABSTRACT: Neuronal microcircuits - small, localized signaling motifs involving two or more neurons - underlie signal processing and computation in the brain. Compartmentalized signaling within a neuron may enable it to participate in multiple, independent microcircuits. Each A17 amacrine cell in the mammalian retina contains within its dendrites hundreds of synaptic feedback microcircuits that operate independently to modulate feedforward signaling in the inner retina. Each of these microcircuits comprises a small (<1 μm) synaptic varicosity that typically receives one excitatory synapse from a presynaptic rod bipolar cell (RBC) and returns two reciprocal inhibitory synapses back onto the same RBC terminal. Feedback inhibition from the A17 sculpts the feedforward signal from the RBC to the AII, a critical component of the circuitry mediating night vision. Here, we show that the two inhibitory synapses from the A17 to the RBC express kinetically distinct populations of GABA receptors: rapidly activating GABAARs are enriched at one synapse while more slowly activating GABACRs are enriched at the other. Anatomical and electrophysiological data suggest that macromolecular complexes of voltage-gated (Cav) channels and Ca(2+)-activated K(+) channels help to regulate GABA release from A17 varicosities and limit GABACR activation under certain conditions. Finally, we find that selective elimination of A17-mediated feedback inhibition reduces the signal to noise ratio of responses to dim flashes recorded in the feedforward pathway (i.e. the AII amacrine cell). We conclude that A17-mediated feedback inhibition improves the signal to noise ratio of RBC-AII transmission near visual threshold, thereby improving visual sensitivity at night. Copyright © 2015, Journal of Neurophysiology.
    Full-text · Article · May 2015 · Journal of Neurophysiology
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