Complex inhibitory microcircuitry regulates retinal signaling near visual threshold

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 GABA(A)Rs are enriched at one synapse while more slowly activating GABA(C)Rs 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 GABA(C)R 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.

Local processing in neurites of VGluT3-expressing amacrine cells differentially organizes visual information

“…Most of the approximately 50 AC types lack separate dendrites and axons and receive input and provide output through the same neurites ( Diamond, 2017 ). Among the few AC types that have been studied in detail, starburst and A17 ACs are critical for direction selectivity and dim light signaling, respectively ( Grimes et al, 2015 ; Amthor et al, 2002 ; Vlasits et al, 2014 ; Yonehara et al, 2016 ; Yoshida et al, 2001 ). The radially symmetric arbors of starburst ACs receive synaptic input and release neurotransmitters near and far from the soma, respectively ( Ding et al, 2016 ; Vlasits et al, 2016 ).…”

Quantifying the effect of light activated outer and inner retinal inhibitory pathways on glutamate release from mixed bipolar cells.

“…Importantly, rod signaling in the goldfish retina saturates around 10 photons/μm 2 /s, whereas S and M cones that also provide input the Mbs produce about half maximal responses at this intensity (Joselevitch & Kamermans, ); therefore, the tested V m responses to light flashes with intensities 1.0, 35, and 1,200 photons/μm 2 /s covered physiologically relevant bright scotopic, mesopic, and photopic stimulus intensities, respectively. Depolarization of BCs has been shown to trigger reciprocal GABAergic feedback from ACs that overlaps I Ca of the BCs in both fish and mammalian retina slices (Grimes et al, ; Vigh et al, ), therefore, to reveal I Ca in its full extent, GABA A and GABA C receptor‐mediated reciprocal chloride conductances in Mb terminals were blocked with PTX (100 µM, Vigh et al, ; Vigh & von Gersdorff, ).…”

A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl− from acidic organelles in amacrine cells

“…Although several families of Cl Ϫ channels and transporters have been identified (Stauber and Jentsch 2013), relatively little is known about their cellular distributions and functional interactions, especially in the context of neurons. Learning more about this will be of particular importance in understanding the function of amacrine cells, because some are capable of highly localized synaptic signaling (Grimes et al 2010(Grimes et al , 2015.…”