Letter | Published:

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

Nature volume 443, pages 705708 (12 October 2006) | Download Citation

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Abstract

Feedback inhibition at reciprocal synapses between A17 amacrine cells and rod bipolar cells (RBCs) shapes light-evoked responses in the retina1,2,3. Glutamate-mediated excitation of A17 cells elicits GABA (γ-aminobutyric acid)-mediated inhibitory feedback onto RBCs4,5,6, 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 release7, 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 (α-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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References

  1. 1.

    & Destruction of the indoleamine-accumulating amacrine cells alters the ERG of rabbits. Invest. Ophthalmol. Vis. Sci. 26, 1109–1116 (1985)

  2. 2.

    & Light-evoked responses of bipolar cells in a mammalian retina. J. Neurophysiol. 83, 1817–1829 (2000)

  3. 3.

    & Temporal modulation of scotopic visual signals by A17 amacrine cells in mammalian retina in vivo. J. Neurophysiol. 89, 2159–2166 (2003)

  4. 4.

    Membrane currents evoked by ionotropic glutamate receptor agonists in rod bipolar cells in the rat retinal slice preparation. J. Neurophysiol. 76, 401–422 (1996)

  5. 5.

    Reciprocal synaptic interactions between rod bipolar cells and amacrine cells in the rat retina. J. Neurophysiol. 81, 2923–2936 (1999)

  6. 6.

    & Sustained Ca2+ entry elicits transient postsynaptic currents at a retinal ribbon synapse. J. Neurosci. 23, 10923–10933 (2003)

  7. 7.

    & The timing of calcium action during neuromuscular transmission. J. Physiol. (Lond.) 189, 535–544 (1967)

  8. 8.

    & Amacrine cells of the cat retina. Vision Res. 21, 1625–1633 (1981)

  9. 9.

    & Molecular specificity of defined types of amacrine synapse in cat retina. J. Neurosci. 6, 1314–1324 (1986)

  10. 10.

    & A17: a broad-field amacrine cell in the rod system of the cat retina. J. Neurophysiol. 54, 592–614 (1985)

  11. 11.

    & A system of indoleamine-accumulating neurons in the rabbit retina. J. Neurosci. 6, 3331–3347 (1986)

  12. 12.

    Morphological identification of serotonin-accumulating neurons in the living retina. Science 233, 444–446 (1986)

  13. 13.

    , , & Coordinated multivesicular release at a mammalian ribbon synapse. Nature Neurosci. 7, 826–833 (2004)

  14. 14.

    & Prolonged reciprocal signalling via NMDA and GABA receptors at a retinal ribbon synapse. J. Neurosci. 25, 11412–11423 (2005)

  15. 15.

    & Surround inhibition of mammalian AII amacrine cells is generated in the proximal retina. J. Physiol. (Lond.) 523, 771–783 (2000)

  16. 16.

    & Spike-dependent GABA inputs to bipolar cell axon terminals contribute to lateral inhibition of retinal ganglion cells. J. Neurophysiol. 89, 2449–2458 (2003)

  17. 17.

    & Morphological and physiological properties of the A17 amacrine cell of the rat retina. Vis. Neurosci. 17, 769–780 (2000)

  18. 18.

    et al. Mode and mechanism of action of neurotoxic indoleamines: a review and a progress report. Ann. NY Acad. Sci. 305, 3–24 (1978)

  19. 19.

    & Dendritic processing within olfactory bulb circuits. Trends Neurosci. 26, 501–506 (2003)

  20. 20.

    & Block of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by polyamines and polyamine toxins. J. Pharmacol. Exp. Ther. 278, 669–678 (1996)

  21. 21.

    Desensitization of the mGluR6 transduction current in tiger salamander On bipolar cells. J. Physiol. (Lond.) 558, 137–146 (2004)

  22. 22.

    , & Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature 311, 538–544 (1984)

  23. 23.

    & Kurtoxin, a gating modifier of neuronal high- and low-threshold ca channels. J. Neurosci. 22, 2023–2034 (2002)

  24. 24.

    , & Selective synaptic distribution of kainate receptor subunits in the two plexiform layers of the rat retina. J. Neurosci. 17, 9298–9307 (1997)

  25. 25.

    , , & Confocal analysis of reciprocal feedback at rod bipolar terminals in the rabbit retina. J. Neurosci. 22, 10871–10882 (2002)

  26. 26.

    & Bafilomycins and concanamycins as inhibitors of V-ATPases and P-ATPases. J. Exp. Biol. 200, 1–8 (1997)

  27. 27.

    & The endoplasmic reticulum as an integrating signalling organelle: from neuronal signalling to neuronal death. Eur. J. Pharmacol. 447, 141–154 (2002)

  28. 28.

    , , , & Calcium from internal stores triggers GABA release from retinal amacrine cells. J. Neurophysiol. 94, 4196–4208 (2005)

  29. 29.

    & Spike timing, calcium signals and synaptic plasticity. Curr. Opin. Neurobiol. 12, 305–314 (2002)

  30. 30.

    & Vesicle depletion and synaptic depression at a mammalian ribbon synapse. J. Neurophysiol. 95, 3191–3198 (2006)

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Acknowledgements

We thank K. Swartz for his gift of kurtoxin, J. Isaac for his gift of GYKI 53655, and J. Isaac, D. Copenhagen, C. Jahr and members of the Diamond laboratory for comments on the manuscript. This research was supported by the NINDS Intramural Research Program and a K22 award to J.H.S. A.E.C. is a doctoral student in a graduate program partnership between NIH and the University of Valparaíso, Chile. Author Contributions A.E.C. and J.H.S. collected and analysed data and helped to design experiments; J.S.D. directed the study, helped to design experiments and wrote the manuscript.

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Author notes

    • Joshua H. Singer

    †Present address: Northwestern University, Departments of Ophthalmology and Physiology, 303 E. Chicago Avenue, Tarry Building, 5-727, Chicago, Illinois 60611, USA

Affiliations

  1. Synaptic Physiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3701, USA

    • Andrés E. Chávez
    • , Joshua H. Singer
    •  & Jeffrey S. Diamond

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeffrey S. Diamond.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    Supplementary Figures 1–4 illustrate experiments that demonstrate the specificity of DHT (Supplementary Fig. 1), the spatial resolution of glutamate puffs (Supplementary Fig. 2), the Cd-sensitivity of glycinergic gIPSCs (Supplementary Fig. 3), and a comparison of different approaches to measure vIPSC amplitude (Supplementary Fig. 4).

  2. 2.

    Supplementary Methods

    Complete description of experimental and analytical methods.

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DOI

https://doi.org/10.1038/nature05123

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