title: 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.
authors.affiliation: Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland; Department of Physiology and Biophysics, Howard Hughes Medical Institute at the University of Washington, Seattle, Washington; and.
authors.forename: William N
authors.initials: WN
authors.lastname: Grimes
authors.affiliation: Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland;
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland;
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.affiliation: Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland;
authors.forename: Cole W
authors.initials: CW
authors.lastname: Graydon
authors.affiliation: Department of Biological Structure, University of Washington, Seattle, Washington.
authors.forename: Mrinalini
authors.initials: M
authors.lastname: Hoon
authors.affiliation: Department of Physiology and Biophysics, Howard Hughes Medical Institute at the University of Washington, Seattle, Washington; and.
authors.forename: Fred
authors.initials: F
authors.lastname: Rieke
authors.affiliation: Synaptic Physiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland; diamondj@ninds.nih.gov.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003624:Darkness; D025461:Feedback, Physiological / Q000502:physiology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010775:Photic Stimulation; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000502:physiology*; D012684:Sensory Thresholds / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D046509:Tissue Culture Techniques; D014785:Vision, Ocular / Q000502:physiology*
chemical_list: D020746:Calcium Channels, L-Type; D051036:Large-Conductance Calcium-Activated Potassium Channels; D018079:Receptors, GABA
keywords: GABA; amacrine; feedback; microcircuit; retina