Fast neurotransmitter release triggered by Ca influx through AMPA-type glutamate receptors

Synaptic Physiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3701, USA.
Nature (Impact Factor: 42.35). 11/2006; 443(7112):705-8. DOI: 10.1038/nature05123
Source: PubMed

ABSTRACT 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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Available from: Jeffrey S Diamond, Aug 17, 2015
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    • "To evoke release of GABA from presynaptic amacrine cells, we puffed a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) at the axon terminal of RBCs (Chá vez et al., 2006) and recorded the evoked PSCs at 0 mV holding potential (Figure 3C). "
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    ABSTRACT: Presynaptic inhibition onto axons regulates neuronal output, but how such inhibitory synapses develop and are maintained in vivo remains unclear. Axon terminals of glutamatergic retinal rod bipolar cells (RBCs) receive GABAA and GABAC receptor-mediated synaptic inhibition. We found that perturbing GABAergic or glutamatergic neurotransmission does not prevent GABAergic synaptogenesis onto RBC axons. But, GABA release is necessary for maintaining axonal GABA receptors. This activity-dependent process is receptor subtype specific: GABAC receptors are maintained, whereas GABAA receptors containing α1, but not α3, subunits decrease over time in mice with deficient GABA synthesis. GABAA receptor distribution on RBC axons is unaffected in GABAC receptor knockout mice. Thus, GABAA and GABAC receptor maintenance are regulated separately. Although immature RBCs elevate their glutamate release when GABA synthesis is impaired, homeostatic mechanisms ensure that the RBC output operates within its normal range after eye opening, perhaps to regain proper visual processing within the scotopic pathway.
    Neuron 04/2013; 78(1):124-37. DOI:10.1016/j.neuron.2013.01.037 · 15.98 Impact Factor
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    • "GABA mediates the predominant inhibitory input to RBCs and subserves both feedback (Vigh and von Gersdorff, 2005; Chavez et al., 2006) and lateral signaling (Eggers and Lukasiewicz, 2006b; Vigh et al., 2011). The spatial dimensions of light-evoked EAATmediated inhibition are unknown, but are likely determined by the extent of spillover transmission from neighboring BCs (Veruki et al., 2006). "
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    ABSTRACT: Excitatory amino acid transporters (EAATs) terminate signaling in the CNS by clearing released glutamate. Glutamate also evokes an EAAT-mediated Cl(-) current, but its role in CNS signaling is poorly understood. We show in mouse retina that EAAT-mediated Cl(-) currents that were evoked by light inhibit rod pathway signaling. EAATs reside on rod bipolar cell axon terminals where GABA and glycine receptors also mediate light-evoked inhibition. We found that the mode of inhibition depended on light intensity. Dim light evoked GABAergic and glycinergic inhibition with rapid kinetics and a large spatial extent. Bright light evoked predominantly EAAT-mediated inhibition with slow kinetics and a small spatial extent. The switch to EAAT-mediated signaling in bright light supplements receptor-mediated signaling to expand the dynamic range of inhibition and contributes to the transition from rod to cone signaling by suppressing rod pathway signaling in bright light conditions.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2012; 32(13):4360-71. DOI:10.1523/JNEUROSCI.5645-11.2012 · 6.75 Impact Factor
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    • "al is sufficiently hyperpolarized to pre - vent further signalling to downstream GCs . To test this idea directly , we recorded from a GC and delivered LY341495 to the dendrites of an ON BC that was vertically aligned with the GC . A similar strategy has been used previously to generate synaptic responses in cells that are postsynaptic to ON BCs ( Chavez et al . 2006 ; Snellman et al . 2009 ) . The first application of LY341495 elicited a robust GC EPSC , while the response to the second application was dramatically reduced ( Fig . 5A ) . The responses of GC recovered as the duration between applications was increased . The rate of recovery could be fitted by a single exponential with a time constan"
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    ABSTRACT: ON bipolar cells invert the sign of light responses from hyperpolarizing to depolarizing before passing them on to ganglion cells. Light responses are generated when a cation channel, recently identified as Trpm1, opens. The amplitude of the light response rapidly decays due to desensitization of Trpm1 current. The role of Trpm1 desensitization in shaping light responses both in bipolar and downstream ganglion cells has not been well characterized. Here we show that two parameters, the amount and the rate of recovery from desensitization, depend on the strength of the presynaptic stimulus. Stimuli that activate less than 20% of the maximum Trpm1 current did not promote any detectable desensitization, even for prolonged periods. Beyond this threshold there was a linear relationship between the amount of desensitization and the fractional Trpm1 current. In response to stimuli that open all available channels, desensitization reduced the response to approximately 40% of the peak, with a time constant of 1 s, and recovery was slow, with a time constant of more than 20 s. In dye-filled bipolar cells classified as transient or sustained using morphological criteria, there were no significant differences in Trpm1 desensitization parameters. Trpm1 activation evoked robust EPSCs in ganglion cells, and removal of Trpm1 desensitization strongly augmented a sustained component of the ganglion cell EPSC irrespective of whether ganglion cells were of the ON or ON/OFF type. We conclude that Trpm1 desensitization impacts the kinetics of ganglion cell EPSCs, but does not underlie the sustained/transient dichotomy of neurons in the ON pathway.
    The Journal of Physiology 01/2012; 590(Pt 1):179-92. DOI:10.1113/jphysiol.2011.218974 · 4.54 Impact Factor
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