Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 443, pages 705–708 (2006)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Reciprocal GABA-mediated synaptic input to RBCs is mediated by A17 amacrine cells.
Figure 2: Calcium-permeable AMPARs trigger GABA release from A17 cells.
Figure 3: Neither membrane depolarization nor VGCC activation triggers GABA release from A17 cells.
Figure 4: Calcium signalling in A17 amacrine cells is amplified by CICR.

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  2. Euler, T. & Masland, R. H. Light-evoked responses of bipolar cells in a mammalian retina. J. Neurophysiol. 83, 1817–1829 (2000)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Kolb, H. & Nelson, R. Amacrine cells of the cat retina. Vision Res. 21, 1625–1633 (1981)

    Article  CAS  Google Scholar 

  9. Sterling, P. & Lampson, L. A. Molecular specificity of defined types of amacrine synapse in cat retina. J. Neurosci. 6, 1314–1324 (1986)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  13. Singer, J. H., Lassova, L., Vardi, N. & Diamond, J. S. Coordinated multivesicular release at a mammalian ribbon synapse. Nature Neurosci. 7, 826–833 (2004)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  19. Schoppa, N. E. & Urban, N. N. Dendritic processing within olfactory bulb circuits. Trends Neurosci. 26, 501–506 (2003)

    Article  CAS  Google Scholar 

  20. Washburn, M. S. & Dingledine, R. 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)

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Hess, P., Lansman, J. B. & Tsien, R. W. Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature 311, 538–544 (1984)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Zhang, J., Li, W., Trexler, E. B. & Massey, S. C. Confocal analysis of reciprocal feedback at rod bipolar terminals in the rabbit retina. J. Neurosci. 22, 10871–10882 (2002)

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Warrier, A., Borges, S., Dalcino, D., Walters, C. & Wilson, M. Calcium from internal stores triggers GABA release from retinal amacrine cells. J. Neurophysiol. 94, 4196–4208 (2005)

    Article  CAS  Google Scholar 

  29. Sjostrom, P. J. & Nelson, S. B. Spike timing, calcium signals and synaptic plasticity. Curr. Opin. Neurobiol. 12, 305–314 (2002)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Joshua H. Singer

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

Authors and 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

Authors
  1. Andrés E. Chávez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua H. Singer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeffrey S. Diamond
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey S. Diamond.

Ethics declarations

Competing interests

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

Supplementary information

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). (PDF 1528 kb)

Supplementary Methods

Complete description of experimental and analytical methods. (PDF 72 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chávez, A., Singer, J. & Diamond, J. Fast neurotransmitter release triggered by Ca influx through AMPA-type glutamate receptors. Nature 443, 705–708 (2006). https://doi.org/10.1038/nature05123

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05123

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing