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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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.
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).
Complete description of experimental and analytical methods.
About this article
Nature Neuroscience (2009)